Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases
Anno: 2026
Rivista: NEURAL REGENERATION RESEARCH
Autori/autrici: Tedeschi, Valentina; Ciancio, Raffaella; Piccirillo, Silvia; Preziuso, Alessandra; Serfilippi, Tiziano; Terenzi, Valentina; Magi, Simona; Lariccia, Vincenzo; Castaldo, Pasqualina; Vinciguerra, Antonio; Piccialli, Ilaria; Canzoniero, Lorella Maria Teresa; Pannaccione, Anna; Secondo, Agnese
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/357515
Citazioni:
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases / Tedeschi, V., Ciancio, R., Piccirillo, S., Preziuso, A., Serfilippi, T., Terenzi, V., Magi, S., Lariccia, V., Castaldo, P., Vinciguerra, A., Piccialli, I., Canzoniero, L.M.T., Pannaccione, A., Secondo, A.. - In: NEURAL REGENERATION RESEARCH. - ISSN 1673-5374. - 21:11(2026), pp. 5142-5151. [10.4103/nrr.nrr-d-25-01754]
Abstract:
Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum ...stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.
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Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)
Anno: 2025
Rivista: STROKE
Autori/autrici: Beretta, Simone; Tettamanti, Mauro; Mariani, Jacopo; Diamanti, Susanna; Valente, Alessia; Cuomo, Ornella; Di Santo, Chiara; Dettori, Ilaria; Venturini, Martina; Bulli, Irene; Coppi, Elisabetta; Alejandro Montano Castillo, Manuel; Butti, Erica; Serena Gullotta, Giorgia; Viganò, Martina; Santangelo, Francesco; Andrea Pedrazzini, Francesco; Perego, Carlo; Seminara, Serena; Anzilotti, Serenella; Rzemieniec, Joanna; Castiglioni, Laura; Mercuriali, Benedetta; Muluhie, Majeda; Paola Zoia, Chiara; Sala, Gessica; Sironi, Luigi; Bacigaluppi, Marco; Martino, Gianvito; Pedata, Felicita; Maria Pugliese, Anna; Amantea, Diana; Bagetta, Giacinto; Vinciguerra, Antonio; Pignataro, Giuseppe; Fumagalli, Stefano; De Simoni, Maria-Grazia; Ferrarese, Carlo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/357512
Citazioni:
Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC) / Beretta, S., Tettamanti, M., Mariani, J., Diamanti, S., Valente, A., Cuomo, O., Di Santo, C., Dettori, I., Venturini, M., Bulli, I., Coppi, E., Alejandro Montano Castillo, M., Butti, E., Serena Gullotta, G., Viganò, M., Santangelo, F., Andrea Pedrazzini, F., Perego, C., Seminara, S., Anzilotti, S., et al.. - In: STROKE. - ISSN 0039-2499. - 56:12(2025), pp. 3342-3351. [10.1161/STROKEAHA.125.051532]
Abstract:
BACKGROUND: Basic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, although clinical evidence remains conflicting. The TRICS BASIC study (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke) investigate...d the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. METHODS: Multicenter, multispecies, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary end point was a good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary end points were infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Preenrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment, and intention-to-treat analysis were applied. RESULTS: The trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across 7 laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared with controls, at 48 hours postischemia (55% versus 36%; odds ratio, 2.2 [95% CI, 1.23–4.4]; P=0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference, −0.38 [95% CI, −0.70 to −0.05]; P=0.024). Health monitoring indicated no major safety concerns, and postoperative analgesia requirements were lower in RIC-treated mice. CONCLUSIONS: Surgically induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity. REGISTRATION: URL: https://www.preclinicaltrials.eu; Unique identifier: PCTE0000177.
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miR135a administration ameliorates brain ischemic damage by preventing TRPM7 activation during brain ischemia
Anno: 2024
Rivista: CNS NEUROSCIENCE & THERAPEUTICS
Autori/autrici: Cepparulo, Pasquale; Brancaccio, Paola; Sirabella, Rossana; Anzilotti, Serenella; Guida, Natascia; Laudati, Gisy; Valsecchi, Valeria.; Vinciguerra, Antonio; Viscardi, Viviana; D'Esposito L., Ucia; Formisano, Luigi; Annunziato, Lucio; Pignataro, Giuseppe; Cuomo, Ornella.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/348254
Citazioni:
miR135a administration ameliorates brain ischemic damage by preventing TRPM7 activation during brain ischemia / Cepparulo, P., Brancaccio, P., Sirabella, R., Anzilotti, S., Guida, N., Laudati, G., Valsecchi, Valeria., Vinciguerra, A., Viscardi, V., D'Esposito L., U., Formisano, L., Annunziato, L., Pignataro, G., Cuomo, Ornella.. - In: CNS NEUROSCIENCE & THERAPEUTICS. - ISSN 1755-5930. - 30:3(2024). [10.1111/cns.14448]
Abstract:
Background: miRNA-based strategies have recently emerged as a promising therapeutic approach in several neurodegenerative diseases. Unregulated cation influx is implicated in several cellular mechanisms underlying neural cell death during ischemia. The brain constitutively active isoform of transien...t receptor potential melastatin 7 (TRPM7) represents a glutamate excitotoxicity-independent pathway that significantly contributes to the pathological Ca2+ overload during ischemia.Aims: In the light of these premises, inhibition of TRPM7 may be a reasonable strategy to reduce ischemic injury. Since TRPM7 is a putative target of miRNA135a, the aim of the present paper was to evaluate the role played by miRNA135a in cerebral ischemia. Therefore, the specific objectives of the present paper were: (1) to evaluate miR135a expression in temporoparietal cortex of ischemic rats; (2) to investigate the effect of the intracerebroventricular (icv) infusion of miR135a on ischemic damage and neurological functions; and (3) to verify whether miR135a effects may be mediated by an alteration of TRPM7 expression.Methods: miR135a expression was evaluated by RT- PCR and FISH assay in temporoparietal cortex of ischemic rats. Ischemic volume and neurological functions were determined in rats subjected to transient middle cerebral artery occlusion (tMCAo) after miR135a intracerebroventricular perfusion. Target analysis was performed by Western blot.Results: Our results demonstrated that, in brain cortex, 72 h after ischemia, miR135a expression increased, while TRPM7 expression was parallelly downregulated. Interestingly, miR135a icv perfusion strongly ameliorated the ischemic damage and improved neurological functions, and downregulated TRPM7 protein levels.Conclusions: The early prevention of TRPM7 activation is protective during brain ischemia.
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Systemic administration of blood-derived exosomes induced by remote ischemic post-conditioning, by delivering a specific cluster of miRNAs, ameliorates ischemic damage and neurological function
Anno: 2024
Rivista: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Autori/autrici: Cuomo, Ornella; Anzilotti, Serenella; Brancaccio, Paola; Cepparulo, Pasquale; Lombardi, Giovanna; Viscardi, Viviana; Vinciguerra, Antonio; Annunziato, Lucio; Pignataro, Giuseppe
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/348252
Citazioni:
Systemic administration of blood-derived exosomes induced by remote ischemic post-conditioning, by delivering a specific cluster of miRNAs, ameliorates ischemic damage and neurological function / Cuomo, O., Anzilotti, S., Brancaccio, P., Cepparulo, P., Lombardi, G., Viscardi, V., Vinciguerra, A., Annunziato, L., Pignataro, G.. - In: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM. - ISSN 0271-678X. - 44:12(2024), pp. 1459-1471. [10.1177/0271678X241270284]
Abstract:
MicroRNAs, contained in exosomes or freely circulating in the plasma, might play a pivotal role in the infarct-sparing effect exerted by remote limb ischemic postconditioning (RLIP). The aims of the present study were: (1) To evaluate the effect of pure exosomes isolated from plasma of animals subje...cted to RLIP systemically administered to ischemic rats; (2) To finely dissect exosomes content in terms of miRNAs; (3) To select those regulatory miRNAs specifically expressed in protective exosomes and to identify molecular pathways involved in their neurobeneficial effects. Circulating exosomes were isolated from blood of animals exposed to RLIP and administered to animals exposed to tMCAO by intracerebroventricular, intraperitoneal or intranasal routes. Exosomal miRNA signature was evaluated by microarray and FISH analysis. Plasmatic exosomes isolated from plasma of RLIP rats attenuated cerebral ischemia reperfusion injury and improved neurological functions until 3 days after ischemia induction. Interestingly, miR-702-3p and miR-423-5p seem to be mainly involved in exosome protective action by modulating NOD1 and NLRP3, two key triggers of neuroinflammation and neuronal death. Collectively, the results of the present work demonstrated that plasma-released exosomes after RLIP may transfer a neuroprotective signal to the brain of ischemic animals, thus representing a potentially translatable therapeutic strategy in stroke.
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Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel
Anno: 2024
Rivista: PHARMACOLOGICAL RESEARCH
Autori/autrici: Tedeschi, Valentina; Nele, Valeria; Valsecchi, Valeria; Anzilotti, Serenella; Vinciguerra, Antonio; Zucaro, Laura; Josè Sisalli, Maria; Cassiano, Chiara; De Iesu, Nunzia; Pignataro, Giuseppe; Maria Teresa Canzoniero, Lorella; Pannaccione, Anna; De Rosa, Giuseppe; Secondo, Agnese
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/337777
Citazioni:
Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel / Tedeschi, V., Nele, V., Valsecchi, V., Anzilotti, S., Vinciguerra, A., Zucaro, L., Josè Sisalli, M., Cassiano, C., De Iesu, N., Pignataro, G., Maria Teresa Canzoniero, L., Pannaccione, A., De Rosa, G., Secondo, A.. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - ELETTRONICO. - 210:(2024), pp. 107491.1-107491.16. [10.1016/j.phrs.2024.107491]
Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. O...f interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1G93A ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca2+]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.
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Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage
Anno: 2024
Rivista: MOLECULAR THERAPY NUCLEIC ACIDS
Autori/autrici: Cepparulo, Pasquale; Cuomo, Ornella; Campani, Virginia; Vinciguerra, Antonio; Sisalli, Maria Josè; Nele, Valeria; Anzilotti, Serenella; Valsecchi, Valeria; Casamassa, Antonella; Brancaccio, Paola; Scorziello, Antonella; De Rosa, Giuseppe; Annunziato, Lucio; Pignataro, Giuseppe
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/348253
Citazioni:
Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage / Cepparulo, P., Cuomo, O., Campani, V., Vinciguerra, A., Sisalli, M.J., Nele, V., Anzilotti, S., Valsecchi, V., Casamassa, A., Brancaccio, P., Scorziello, A., De Rosa, G., Annunziato, L., Pignataro, G.. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - 35:1(2024). [10.1016/j.omtn.2024.102131]
Abstract:
MicroRNA (miRNA), by post-transcriptionally regulating the expression of genes involved in stroke response, represents important effectors in stroke pathophysiology. Recently, the 103/107 miRNA family emerged as a possible therapeutic target in stroke, as it controls the expression of sodium calcium... exchanger 1, a plasma membrane transporter that plays a fundamental role in stroke pathophysiology. Although the neuroprotective properties of this and other miRNAs are promising, several pharmacokinetic drawbacks remain to be faced for the development of a translatable therapy based on small RNAs in CNS diseases. In the present study, to overcome these limitations, the anti-miRNA103/107 was encapsulated in specific preparations of lipid nanoparticles (LNPs), and their effectiveness was evaluated both in an in vitro model of hypoxia represented by primary neuronal cortical cultures exposed to oxygen and glucose deprivation followed by reoxygenation, and in an in vivo model of stroke obtained in rats exposed to transient occlusion of the middle cerebral artery. The results of the present study demonstrated that the encapsulation of anti-miRNA103/107 in transferrin-conjugated PEG-stabilized LNPs allowed the blood-brain barrier crossing and significantly reduced brain ischemic damage. The present achievements pave the way for the exploitation of a systemic intravenous miRNA delivery strategy in stroke therapy.
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Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease
Anno: 2023
Rivista: BIOLOGY
Autori/autrici: Preziuso, Alessandra; Piccirillo, Silvia; Cerqueni, Giorgia; Serfilippi, Tiziano; Terenzi, Valentina; Vinciguerra, Antonio; Orciani, Monia; Amoroso, Salvatore; Magi, Simona; Lariccia, Vincenzo
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/321551
Citazioni:
Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease / Preziuso, A., Piccirillo, S., Cerqueni, G., Serfilippi, T., Terenzi, V., Vinciguerra, A., Orciani, M., Amoroso, S., Magi, S., Lariccia, V.. - In: BIOLOGY. - ISSN 2079-7737. - 12:7(2023). [10.3390/biology12071005]
Abstract:
Simple Summary Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the most common cause of dementia among elderly people. It is characterized by the deterioration of brain cells and is linked to problems with energy production, cell metabolism, and harmful oxida...tive stress. Our study focused on two proteins called NCX1 and NCX3, which play a role in controlling calcium and sodium levels in cells. We wanted to understand whether these proteins may be involved in AD development when brain cells are exposed to metabolic impairment. To investigate this, we used a laboratory cell model and treated the cells with a substance called glyceraldehyde (GA) to mimic the metabolic dysfunction seen in AD. We used a technique called RNA interference to silence the expression of either NCX1 or NCX3 in the cells. We found that when NCX3 was silenced, the cells showed improved viability, increased energy production, and reduced damage from oxidative stress. Additionally, the levels of abnormal proteins associated with AD, such as A & beta; and pTau, were decreased. However, silencing NCX1 did not have the same positive effects, except for increased energy production. These findings suggest that targeting NCX3 may be a potential strategy to prevent the development of AD associated with metabolic dysfunction. Considering the paucity of pharmacological therapies, this knowledge could be valuable for identifying new potential treatments for AD. Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes A & beta; deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of A & beta; and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.
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Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation
Anno: 2023
Rivista: NEUROBIOLOGY OF DISEASE
Autori/autrici: Tedeschi, Valentina; Vinciguerra, Antonio; José Sisalli, Maria; Pignataro, Giuseppe; Secondo, Agnese
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/329197
Citazioni:
Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation / Tedeschi, V., Vinciguerra, A., José Sisalli, M., Pignataro, G., Secondo, A.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 178:(2023). [10.1016/j.nbd.2023.106020]
Abstract:
Lysosomal function and organellar Ca2+ homeostasis become dysfunctional in Stroke causing disturbances in autophagy, the major process for the degradation of abnormal protein aggregates and dysfunctional organelles. However, the role of autophagy in Stroke is controversial since excessive or prolong...ed autophagy activation exacerbates ischemic brain injury. Of note, glutamate evokes NAADP-dependent Ca2+ release via lysosomal TPC2 channels thus controlling basal autophagy. Considering the massive release of excitotoxins in Stroke, autophagic flux becomes uncontrolled with abnormal formation of autophagosomes causing, in turn, disruption of excitotoxins clearance and neurodegeneration. Here, a fine regulation of autophagy via a proper pharmacological modulation of lysosomal TPC2 channel has been tested in preclinical Stroke models. Primary cortical neurons were subjected to oxygen and glucose deprivation+reoxygenation to reproduce in vitro brain ischemia. Focal brain ischemia was induced in rats by transient middle cerebral artery occlusion (tMCAO). Under these conditions, TPC2 protein expression as well as autophagy and endoplasmic reticulum (ER) stress markers were studied by Western blotting, while TPC2 localization and activity were measured by immunocytochemistry and single-cell video-imaging, respectively. TPC2 protein expression and immunosignal were highly modulated in primary cortical neurons exposed to extreme hypoxic conditions causing dysfunction in organellar Ca2+ homeostasis, ER stress and autophagy-induced cell death. TPC2 knocking down and pharmacological inhibition by Ned-19 during hypoxia induced neuroprotection. The effect of Ned-19 was reversed by the permeable form of TPC2 endogenous agonist, NAADP-AM. Of note, Ned-19 prevented ER stress, as measured by GRP78 (78 kDa glucose-regulated protein) protein reduction and caspase 9 downregulation. In this way Ned-19 restored organellar Ca2+ level. Interestingly, Ned-19 reduced the infarct volume and neurological deficits in rats subjected to tMCAO and prevented hypoxia-induced cell death by blocking autophagic flux. Collectively, the pharmacological inhibition of TPC2 lysosomal channel by Ned-19 protects from focal ischemia by hampering a hyperfunctional autophagy.
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A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde
Anno: 2023
Rivista: BIOCHEMICAL PHARMACOLOGY
Autori/autrici: Piccirillo, Silvia; Preziuso, Alessandra; Cerqueni, Giorgia; Serfilippi, Tiziano; Terenzi, Valentina; Vinciguerra, Antonio; Amoroso, Salvatore; Lariccia, Vincenzo; Magi, Simona
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/325811
Citazioni:
A strategic tool to improve the study of molecular determinants of Alzheimer's disease: The role of glyceraldehyde / Piccirillo, S., Preziuso, A., Cerqueni, G., Serfilippi, T., Terenzi, V., Vinciguerra, A., Amoroso, S., Lariccia, V., Magi, S.. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 1873-2968. - ELETTRONICO. - 218:(2023). [10.1016/j.bcp.2023.115869]
Abstract:
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammatio...n, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.
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Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke
Anno: 2023
Rivista: JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM
Autori/autrici: Valente, A.; Mariani, J.; Seminara, S.; Tettamanti, M.; Pignataro, G.; Perego, C.; L., Sironi; Pedata, F.; Amantea, D.; Bacigaluppi, M.; Vinciguerra, A.; Diamanti, S.; Vigano, M.; Santangelo, F.; Zoia, C. P.; Rodriguez-Menendez, V.; Castiglioni, L.; J., Rzemieniec; Dettori, I.; Bulli, I.; Coppi, E.; Di Santo, C.; Cuomo, O.; Gullotta, G. S.; Butti, E.; Bagetta, G.; Martino, G.; De Simoni, M. -G.; Ferrarese, C.; Fumagalli, S.; Beretta, S
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/329198
Citazioni:
Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke / Valente, A., Mariani, J., Seminara, S., Tettamanti, M., Pignataro, G., Perego, C., L., S., Pedata, F., Amantea, D., Bacigaluppi, M., Vinciguerra, A., Diamanti, S., Vigano, M., Santangelo, F., Zoia, C.P., Rodriguez-Menendez, V., Castiglioni, L., J., R., Dettori, I., Bulli, I., et al.. - In: JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM. - ISSN 1559-7016. - 43:7(2023). [10.1177/0271678X231159958]
Abstract:
Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantifi...cation of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke. Ischemic stroke was induced by middle cerebral artery occlusion for 30, 45 or 60 min in mice and 50, 75 or 100 min in rats, allowing sufficient variability. Eleven animals per species were video recorded during neurobehavioural tasks and evaluated with neuroscore by eight independent raters, remotely and blindly. We aimed at reaching an intraclass correlation coefficient (ICC) ≥0.60 as satisfactory interrater agreement. After a first remote training we obtained ICC = 0.50 for mice and ICC = 0.49 for rats. Errors were identified in animal handling and test execution. After a second remote training, we reached the target interrater agreement for mice (ICC = 0.64) and rats (ICC = 0.69). In conclusion, a multi-step, online harmonization phase proved to be feasible, easy to implement and highly effective to align each centre’s behavioral evaluations before project’s interventional phase.
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Preconditioning in hypoxic-ischemic neonate mice triggers Na+-Ca2+ exchanger-dependent neurogenesis
Anno: 2022
Rivista: CELL DEATH DISCOVERY
Autori/autrici: Brancaccio, P; Anzilotti, S; Cuomo, O; Vinciguerra, A; Campanile, M; Herchuelz, A; Amoroso, S; Annunziato, L; Pignataro, G
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/314491
Citazioni:
Preconditioning in hypoxic-ischemic neonate mice triggers Na+-Ca2+ exchanger-dependent neurogenesis / Brancaccio, P., Anzilotti, S., Cuomo, O., Vinciguerra, A., Campanile, M., Herchuelz, A., Amoroso, S., Annunziato, L., Pignataro, G.. - In: CELL DEATH DISCOVERY. - ISSN 2058-7716. - 8:1(2022).
Abstract:
To identify alternative interventions in neonatal hypoxic-ischemic encephalopathy, researchers' attention has been focused to the study of endogenous neuroprotective strategies. Based on the preconditioning concept that a subthreshold insult may protect from a subsequent harmful event, we aimed... at identifying a new preconditioning protocol able to enhance Ca2+-dependent neurogenesis in a mouse model of neonatal hypoxia ischemia (HI). To this purpose, we also investigated the role of the preconditioning-linked protein controlling ionic homeostasis, Na+/Ca2+ exchanger (NCX). Hypoxic Preconditioning (HPC) was reproduced by exposing P7 mice to 20' hypoxia. HI was induced by isolating and cutting the right common carotid artery. A significant reduction in ischemic damage was observed in mice subjected to 20' hypoxia followed,3 days later, by 60' HI, thus suggesting that 20' hypoxia functions as preconditioning stimulus. HPC promoted neuroblasts proliferation in the dentate gyrus mirrored by an increase of NCX1 and NCX3-positive cells and an improvement of behavioral motor performances in HI mice. An attenuation of HPC neuroprotection as well as a reduction in the expression of neurogenesis markers, including p57 and NeuroD1, was observed in preconditioned mice lacking NCX1 or NCX3. In summary, PC in neonatal mice triggers a neurogenic process linked to ionic homeostasis maintenance, regulated by NCX1 and NCX3.
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Ruta graveolens water extract (RGWE) ameliorates ischemic damage and improves neurological deficits in a rat model of transient focal brain ischemia
Anno: 2022
Rivista: BIOMEDICINE & PHARMACOTHERAPY
Autori/autrici: Campanile, Mario; Cuomo, Ornella; Brancaccio, Paola; Vinciguerra, Antonio; Casamassa, Antonella; Pastorino, Olga; Volpicelli, Floriana; Gentile, Maria Teresa; Amoroso, Salvatore; Annunziato, Lucio; Colucci-D Amato, Luca; Pignataro, Giuseppe
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/314493
Citazioni:
Ruta graveolens water extract (RGWE) ameliorates ischemic damage and improves neurological deficits in a rat model of transient focal brain ischemia / Campanile, M., Cuomo, O., Brancaccio, P., Vinciguerra, A., Casamassa, A., Pastorino, O., Volpicelli, F., Gentile, M.T., Amoroso, S., Annunziato, L., Colucci-D Amato, L., Pignataro, G.. - In: BIOMEDICINE & PHARMACOTHERAPY. - ISSN 1950-6007. - 154:(2022). [10.1016/j.biopha.2022.113587]
Abstract:
Introduction and aims: The limited therapeutic options for ischemic stroke treatment render necessary the identification of new strategies. In recent years, it has been shown that natural compounds may represent a valid therapeutic opportunity. Therefore, the present study aimed to evaluate the prot...ective effect of Ruta graveolens water extract (RGWE) in an in vivo experimental model of brain ischemia. Methods: RGWE effects on ischemic damage and neurological function were evaluated in adult rats subjected to transient occlusion of the Middle Cerebral Artery (tMCAO), receiving two intraperitoneal injections of RGWE, 100 and 300 min after the induction of ischemia. In addition, astroglial and microglial activation was measured as GFAP and IBA-1 expression by immunofluorescence and confocal microscopy analysis. Results: Treatment with RGWE containing 10 mg/kg of Rutin, the major component, ameliorates the ischemic damage and improves neurological performances. Interestingly, the pro-inflammatory states of astrocytes and microglia, respectively detected by using C3 and iNOS markers, were significantly reduced in ipsilateral cortical and striatal areas in ischemic RGWE-treated rats. Conclusions: RGWE shows a neuroprotective effect on brain infarct volume extent in a transient focal cerebral ischemia model and this effect was paralleled by the prevention of pro-inflammatory astroglial and microglial activation. Collectively, our findings support the idea that natural compounds may represent potential therapeutic opportunities against ischemic stroke.
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miR-16-5p, miR-103-3p, and miR-27b-3p as Early Peripheral Biomarkers of Fetal Growth Restriction
Anno: 2021
Rivista: FRONTIERS IN PEDIATRICS
Autori/autrici: Tagliaferri, S.; Cepparulo, P.; Vinciguerra, A.; Campanile, M.; Esposito, G.; Maruotti, G. M.; Zullo, F.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289883
Citazioni:
miR-16-5p, miR-103-3p, and miR-27b-3p as Early Peripheral Biomarkers of Fetal Growth Restriction / Tagliaferri, S., Cepparulo, P., Vinciguerra, A., Campanile, M., Esposito, G., Maruotti, G.M., Zullo, F., Annunziato, L., Pignataro, G.. - In: FRONTIERS IN PEDIATRICS. - ISSN 2296-2360. - ELETTRONICO. - 9:(2021). [10.3389/fped.2021.611112]
Abstract:
Current tests available to diagnose fetal hypoxia in-utero lack sensitivity thus failing to identify many fetuses at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may be used as non-invasive biomarkers for pregnancy com...plications. With the intent to identify putative markers of fetal growth restriction (FGR) and new therapeutic druggable targets, we examined, in maternal blood samples, the expression of a group of microRNAs, known to be regulated by hypoxia. The expression of microRNAs was evaluated in maternal plasma samples collected from (1) women carrying a preterm FGR fetus (FGR group) or (2) women with an appropriately grown fetus matched at the same gestational age (Control group). To discriminate between early- and late-onset FGR, the study population was divided into two subgroups according to the gestational age at delivery. Four microRNAs were identified as possible candidates for the diagnosis of FGR: miR-16-5p, miR-103-3p, miR-107-3p, and miR-27b-3p. All four selected miRNAs, measured by RT-PCR, resulted upregulated in FGR blood samples before the 32nd week of gestation. By contrast, miRNA103-3p and miRNA107-3p, analyzed between the 32nd and 37th week of gestation, showed lower expression in the FGR group compared to aged matched controls. Our results showed that measurement of miRNAs in maternal blood may form the basis for a future diagnostic test to determine the degree of fetal hypoxia in FGR, thus allowing the start of appropriate therapeutic interventions to alleviate the burden of this disease.
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Plasma membrane and organellar targets of stim1 for intracellular calcium handling in health and neurodegenerative diseases
Anno: 2021
Rivista: CELLS
Autori/autrici: Tedeschi, V.; La Russa, D.; Franco, C.; Vinciguerra, A.; Amantea, D.; Secondo, A.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/299509
Citazioni:
Plasma membrane and organellar targets of stim1 for intracellular calcium handling in health and neurodegenerative diseases / Tedeschi, V., La Russa, D., Franco, C., Vinciguerra, A., Amantea, D., Secondo, A.. - In: CELLS. - ISSN 2073-4409. - 10:10(2021), p. 2518. [10.3390/cells10102518]
Abstract:
Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER‐plasma membrane (PM) junctions where it directly interacts with and... activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store‐operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L‐type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.
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Synthesis and Characterization of Novel Mono- And Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult
Anno: 2021
Rivista: JOURNAL OF MEDICINAL CHEMISTRY
Autori/autrici: Gornati, D.; Ciccone, R.; Vinciguerra, A.; Ippati, S.; Pannaccione, A.; Petrozziello, T.; Pizzi, E.; Hassan, A.; Colombo, E.; Barbini, S.; Milani, M.; Caccavone, C.; Randazzo, P.; Muzio, L.; Annunziato, L.; Menegon, A.; Secondo, A.; Mastrangelo, E.; Pignataro, G.; Seneci, P.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/299508
Citazioni:
Synthesis and Characterization of Novel Mono- And Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult / Gornati, D., Ciccone, R., Vinciguerra, A., Ippati, S., Pannaccione, A., Petrozziello, T., Pizzi, E., Hassan, A., Colombo, E., Barbini, S., Milani, M., Caccavone, C., Randazzo, P., Muzio, L., Annunziato, L., Menegon, A., Secondo, A., Mastrangelo, E., Pignataro, G., Seneci, P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:12(2021), pp. 8333-8353. [10.1021/acs.jmedchem.1c00305]
Abstract:
Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca2+ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury.... We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmedin vitro, on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, andin vivo, in ischemic mice. Early lead 3b, showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice.
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Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream
Anno: 2021
Rivista: FRONTIERS IN NEUROLOGY
Autori/autrici: Cepparulo, P.; Cuomo, O.; Vinciguerra, A.; Torelli, M.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/299510
Citazioni:
Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream / Cepparulo, P., Cuomo, O., Vinciguerra, A., Torelli, M., Annunziato, L., Pignataro, G.. - In: FRONTIERS IN NEUROLOGY. - ISSN 1664-2295. - 12:(2021). [10.3389/fneur.2021.736474]
Abstract:
To date, the only effective pharmacological treatment for ischemic stroke is limited to the clinical use of recombinant tissue plasminogen activator (rtPA), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke. Unfortunately, the benefit of this treatmen...t is limited to a 4.5-h time window. Most importantly, the use of rtPA is contraindicated in the case of hemorrhagic stroke. Therefore, the identification of a reliable biomarker to distinguish hemorrhagic from ischemic stroke could provide several advantages, including an earlier diagnosis, a better treatment, and a faster decision on ruling out hemorrhage so that tPA may be administered earlier. microRNAs (miRNAs) are stable non-coding RNAs crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression. In the present paper, taking advantage of three preclinical animal models of stroke, we compared the miRNA blood levels of animals subjected to permanent or transient middle cerebral artery occlusion (MCAO) or to collagenase-induced hemorrhagic stroke. Preliminarily, we examined the rat miRNome in the brain tissue of ischemic and sham-operated rats; then, we selected those miRNAs whose expression was significantly modulated after stroke to create a list of miRNAs potentially involved in stroke damage. These selected miRNAs were then evaluated at different time intervals in the blood of rats subjected to permanent or transient focal ischemia or to hemorrhagic stroke. We found that four miRNAs—miR-16-5p, miR-101a-3p, miR-218-5p, and miR-27b-3p—were significantly upregulated in the plasma of rats 3 h after permanent MCAO, whereas four other different miRNAs—miR-150-5p, let-7b-5p, let-7c-5p, and miR-181b-5p—were selectively upregulated by collagenase-induced hemorrhagic stroke. Collectively, our study identified some selective miRNAs expressed in the plasma of hemorrhagic rats and pointed out the importance of a precise time point measurement to render more reliable the use of miRNAs as stroke biomarkers.
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Remote postconditioning ameliorates stroke damage by preventing let-7a and miR-143 up-regulation
Anno: 2020
Rivista: THERANOSTICS
Autori/autrici: Vinciguerra, A.; Cepparulo, P.; Anzilotti, S.; Cuomo, O.; Valsecchi, V.; Amoroso, S.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289887
Citazioni:
Remote postconditioning ameliorates stroke damage by preventing let-7a and miR-143 up-regulation / Vinciguerra, A., Cepparulo, P., Anzilotti, S., Cuomo, O., Valsecchi, V., Amoroso, S., Annunziato, L., Pignataro, G.. - In: THERANOSTICS. - ISSN 1838-7640. - 10:26(2020), pp. 12174-12188. [10.7150/thno.48135]
Abstract:
Remote limb ischemic postconditioning (RLIP) is a well-established neuroprotective strategy able to protect the brain from a previous harmful ischemic insult through a sub-lethal occlusion of the femoral artery. Neural and humoral mechanisms have been proposed as mediators required to transmit the p...eripheral signal from limb to brain. Moreover, different studies suggest that protection observed at brain level is associated to a general genetic reprogramming involving also microRNAs (miRNAs) intervention. Methods: Brain ischemia was induced in male rats by transient occlusion of the middle cerebral artery (tMCAO), whereas RLIP was achieved by one cycle of temporary occlusion of the ipsilateral femoral artery after tMCAO. The expression profile of 810 miRNAs was evaluated in ischemic brain samples from rats subjected either to tMCAO or to RLIP. Among all analyzed miRNAs, there were four whose expression were upregulated after stroke and returned to basal level after RLIP, thus suggesting a possible involvement in RLIP-induced neuroprotection. These selected miRNAs were intracerebroventricularly infused in rats subjected to remote ischemic postconditioning, and their effect was evaluated in terms of brain damage, neurological deficit scores and expression of putative targets. Results: Twenty-one miRNAs, whose expression was significantly affected by tMCAO and by tMCAO plus RLIP, were selected based on microarray microfluidic profiling. Our data showed that: (1) stroke induced an up-regulation of let-7a and miR-143 (2) these two miRNAs were involved in the protective effects induced by RLIP and (3) HIF1-α contributes to their protective effect. Indeed, their expression was reduced after RLIP and the exogenous intracerebroventricularly infusion of let-7a and miR-143 mimics prevented neuroprotection and HIF1-α overexpression induced by RLIP. Conclusions: Prevention of cerebral let-7a and miR-143 overexpression induced by brain ischemia emerges as new potential strategy in stroke intervention.
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Sumoylation of sodium/calcium exchanger in brain ischemia and ischemic preconditioning
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Cuomo, O.; Casamassa, A.; Brancaccio, P.; Laudati, G.; Valsecchi, V.; Anzilotti, S.; Vinciguerra, A.; Pignataro, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289885
Citazioni:
Sumoylation of sodium/calcium exchanger in brain ischemia and ischemic preconditioning / Cuomo, O., Casamassa, A., Brancaccio, P., Laudati, G., Valsecchi, V., Anzilotti, S., Vinciguerra, A., Pignataro, G., Annunziato, L.. - In: CELL CALCIUM. - ISSN 0143-4160. - ELETTRONICO. - 87:(2020), p. 102195. [10.1016/j.ceca.2020.102195]
Abstract:
The small ubiquitin-like modifier (SUMO) conjugation (or SUMOylation) is a post-translational protein modification mechanism activated by different stress conditions that has been recently investigated in experimental models of cerebral ischemia. The expression of SUMOylation enzymes and substrates ...is not restricted to the nucleus, since they are present also in the cytoplasm and on plasma membrane and are involved in several physiological and pathological conditions. In the last decades, convincing evidence have supported the idea that the increased levels of SUMOylated proteins may induce tolerance to ischemic stress. In particular, it has been established that protein SUMOylation may confer neuroprotection during ischemic preconditioning. Considering the increasing evidence that SUMO can modify stability and expression of ion channels and transporters and the relevance of controlling ionic homeostasis in ischemic conditions, the present review will resume the main aspects of SUMO pathways related to the key molecules involved in maintenance of ionic homeostasis during cerebral ischemia and ischemic preconditioning, with a particular focus on the on Na+/Ca2+ exchangers.
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Sodium/calcium exchanger as main effector of endogenous neuroprotection elicited by ischemic tolerance
Anno: 2020
Rivista: CELL CALCIUM
Autori/autrici: Pignataro, G.; Brancaccio, P.; Laudati, G.; Valsecchi, V.; Anzilotti, S.; Casamassa, A.; Cuomo, O.; Vinciguerra, A.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289884
Citazioni:
Sodium/calcium exchanger as main effector of endogenous neuroprotection elicited by ischemic tolerance / Pignataro, G., Brancaccio, P., Laudati, G., Valsecchi, V., Anzilotti, S., Casamassa, A., Cuomo, O., Vinciguerra, A.. - In: CELL CALCIUM. - ISSN 0143-4160. - ELETTRONICO. - 87:(2020). [10.1016/j.ceca.2020.102183]
Abstract:
The ischemic tolerance (IT) paradigm represents a fundamental cell response to certain types or injury able to render an organ more “tolerant” to a subsequent, stronger, insult. During the 16th century, the toxicologist Paracelsus described for the first time the possibility that a noxio...us event might determine a state of tolerance. This finding was summarized in one of his most important mentions: “The dose makes the poison”. In more recent years, ischemic tolerance in the brain was first described in 1991, when it was demonstrated by Kirino and collaborators that two minutes of subthreshold brain ischemia in gerbils produced tolerance against global brain ischemia. Based on the time in which the conditioning stimulus is applied, it is possible to define preconditioning, perconditioning and postconditioning, when the subthreshold insult is applied before, during or after the ischemic event, respectively. Furthermore, depending on the temporal delay from the ischemic event, two different modalities are distinguished: rapid or delayed preconditioning and postconditioning. Finally, the circumstance in which the conditioning stimulus is applied on an organ distant from the brain is referred as remote conditioning. Over the years the “conditioning” paradigm has been applied to several brain disorders and a number of molecular mechanisms taking part to these protective processes have been described. The mechanisms are usually classified in three distinct categories identified as triggers, mediators and effectors. As concerns the putative effectors, it has been hypothesized that brain cells appear to have the ability to adapt to hypoxia by reducing their energy demand through modulation of ion channels and transporters, which delays anoxic depolarization. The purpose of the present review is to summarize the role played by plasmamembrane proteins able to control ionic homeostasis in mediating protection elicited by brain conditioning, particular attention will be deserved to the role played by Na+/Ca2+ exchanger.
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Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory
Anno: 2020
Rivista: MOLECULAR NEUROBIOLOGY
Autori/autrici: Natale, S.; Anzilotti, S.; Petrozziello, T.; Ciccone, R.; Serani, A.; Calabrese, L.; Severino, B.; Frecentese, F.; Secondo, A.; Pannaccione, A.; Fiorino, F.; Cuomo, O.; Vinciguerra, A.; D'Esposito, L.; Sadile, A. G.; Cabib, S.; Di Renzo, G.; Annunziato, L.; Molinaro, P.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289886
Citazioni:
Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory / Natale, S., Anzilotti, S., Petrozziello, T., Ciccone, R., Serani, A., Calabrese, L., Severino, B., Frecentese, F., Secondo, A., Pannaccione, A., Fiorino, F., Cuomo, O., Vinciguerra, A., D'Esposito, L., Sadile, A.G., Cabib, S., Di Renzo, G., Annunziato, L., Molinaro, P.. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - 57:5(2020), pp. 2358-2376. [10.1007/s12035-020-01888-4]
Abstract:
The Na+/Ca2+ exchanger 1 (NCX1) participates in the maintenance of neuronal Na+ and Ca2+ homeostasis, and it is highly expressed at synapse level of some brain areas involved in learning and memory processes, including the hippocampus, cortex, and amygdala. Furthermore, NCX1 increases Akt1 phosphory...lation and enhances glutamate-mediated Ca2+ influx during depolarization in hippocampal and cortical neurons, two processes involved in learning and memory mechanisms. We investigated whether the modulation of NCX1 expression/activity might influence learning and memory processes. To this aim, we used a knock-in mouse overexpressing NCX1 in hippocampal, cortical, and amygdala neurons (ncx1.4over) and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both ncx1.4over and CN-PYB2-treated mice showed an amelioration in spatial learning performance in Barnes maze task, and in context-dependent memory consolidation after trace fear conditioning. On the other hand, these mice showed no improvement in novel object recognition task which is mainly dependent on non-spatial memory and displayed an increase in the active phosphorylated CaMKIIα levels in the hippocampus. Interestingly, both of these mice showed an increased level of context-dependent anxiety. Altogether, these results demonstrate that neuronal NCX1 participates in spatial-dependent hippocampal learning and memory processes.
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Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats
Anno: 2019
Rivista: MOLECULAR THERAPY NUCLEIC ACIDS
Autori/autrici: Cuomo, O.; Cepparulo, P.; Anzilotti, S.; Serani, A.; Sirabella, R.; Brancaccio, P.; Guida, N.; Valsecchi, V.; Vinciguerra, A.; Molinaro, P.; Formisano, L.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/289888
Citazioni:
Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats / Cuomo, O., Cepparulo, P., Anzilotti, S., Serani, A., Sirabella, R., Brancaccio, P., Guida, N., Valsecchi, V., Vinciguerra, A., Molinaro, P., Formisano, L., Annunziato, L., Pignataro, G.. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - 18:(2019), pp. 1063-1071. [10.1016/j.omtn.2019.10.022]
Abstract:
It has been demonstrated that the K+-dependent Na+/Ca2+ exchanger, NCKX2, is a new promising stroke neuroprotective target. However, because no pharmacological activator of NCKX2 is still available, microRNA (miRNA) may represent an alternative method to modulate NCKX2 expression. In particular, by ...bioinformatics analysis, miR-223-5p emerged as a possible modulator of NCKX2 expression. In the light of these premises, the aims of the present study were: (1) to evaluate miR-223-5p and NCKX2 expression in the temporoparietal cortex and striatum of rats subjected to transient middle cerebral artery occlusion; (2) to evaluate whether miR-223-5p targets the 3′ UTR of the NCKX2 transcript; and (3) to evaluate the effect of miR-223-5p modulation on brain ischemic volume and neurological deficits. Our results showed that miR-223-5p expression increased in a time-dependent manner in the striatum of ischemic rats in parallel with NCKX2 downregulation, and that the transfection of cortical neurons with miR-223-5p induced a reduction of NCKX2 expression. Moreover, a luciferase assay showed that miR-223-5p specifically interacts with the NCKX2 3′ UTR subregion (+7037 to +8697), thus repressing NCKX2 translation. More interestingly, intracerebroventricular infusion of anti-miR-223-5p prevented NCKX2 downregulation after ischemia, thus promoting neuroprotection. The present findings support the idea that blocking miR-223-5p by antimiRNA is a reasonable strategy to reduce the neurodetrimental effect induced by NCKX2 downregulation during brain ischemia.
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ORAI1/STIM1 Interaction Intervenes in Stroke and in Neuroprotection Induced by Ischemic Preconditioning Through Store-Operated Calcium Entry
Anno: 2019
Rivista: STROKE
Autori/autrici: Secondo, A.; Petrozziello, T.; Tedeschi, V.; Boscia, F.; Vinciguerra, A.; Ciccone, R.; Pannaccione, A.; Molinaro, P.; Pignataro, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283080
Citazioni:
ORAI1/STIM1 Interaction Intervenes in Stroke and in Neuroprotection Induced by Ischemic Preconditioning Through Store-Operated Calcium Entry / Secondo, A., Petrozziello, T., Tedeschi, V., Boscia, F., Vinciguerra, A., Ciccone, R., Pannaccione, A., Molinaro, P., Pignataro, G., Annunziato, L.. - In: STROKE. - ISSN 0039-2499. - 50:5(2019), pp. 1240-1249. [10.1161/STROKEAHA.118.024115]
Abstract:
Background and Purpose - Disturbance of endoplasmic reticulum (ER) Ca2+ homeostasis causes neuronal cell injury in stroke. By contrast, ischemic preconditioning (IPC) - a brief sublethal ischemic episode affording tolerance to a subsequent ischemic insult - restores ER Ca2+ homeostasis. Under physio...logical conditions, ER calcium content is continuously refilled by the interaction between the ER-located Ca2+ sensor STIM (stromal interacting molecule) 1 and the plasma membrane channel ORAI1 (a structural component of the CRAC calcium channel) - 2 key mediators of the store-operated calcium entry (SOCE) mechanism. However, the role played by ORAI1 and STIM1 in stroke and in IPC-induced neuroprotection during stroke remains unknown. Therefore, we explored whether ORAI1 and STIM1 might be involved in stroke pathogenesis and in IPC-induced neuroprotection. Methods - Primary cortical neurons were subjected to oxygen and glucose deprivation+reoxygenation to reproduce in vitro brain ischemia. Focal brain ischemia and IPC were induced in rats by transient middle cerebral artery occlusion. Expression of ORAI1 and STIM1 transcripts and proteins and their immunosignals were detected by qRT-PCR, Western blot, and immunocytochemistry, respectively. SOCE and Ca2+ release-activated Ca2+ currents (ICRAC) were measured by Fura-2 AM video imaging and patch-clamp electrophysiology in whole-cell configuration, respectively. Results - STIM1 and ORAI1 protein expression and immunosignals decreased in the ipsilesional temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion followed by reperfusion. Analogously, in primary hypoxic cortical neurons, STIM1 and ORAI1 transcript and protein levels decreased concurrently with SOCE and Ca2+ release-activated Ca2+currents. By contrast, IPC induced SOCE and Ca2+ release-activated Ca2+current upregulation, thereby preventing STIM1 and ORAI1 downregulation induced by oxygen and glucose deprivation+reoxygenation. Silencing of STIM1 or ORAI1 prevented IPC-induced tolerance and caused ER stress, as measured by GRP78 (78-kDa glucose regulated protein) and caspase-3 upregulation. Conclusions - ORAI1 and STIM1, which participate in SOCE, take part in stroke pathophysiology and play an important role in IPC-induced neuroprotection.
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Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia
Anno: 2018
Rivista: NEUROPHARMACOLOGY
Autori/autrici: Cerullo, P.; Brancaccio, P.; Anzilotti, S.; Vinciguerra, A.; Cuomo, O.; Fiorino, F.; Severino, B.; Di Vaio, P.; Di Renzo, G.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283110
Citazioni:
Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia / Cerullo, P., Brancaccio, P., Anzilotti, S., Vinciguerra, A., Cuomo, O., Fiorino, F., Severino, B., Di Vaio, P., Di Renzo, G., Annunziato, L., Pignataro, G.. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 135:(2018), pp. 180-191. [10.1016/j.neuropharm.2018.03.017]
Abstract:
Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult bra...in ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.
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Ionic homeostasis maintenance in ALS: Focus on new therapeutic targets
Anno: 2018
Rivista: FRONTIERS IN NEUROSCIENCE
Autori/autrici: Sirabella, R.; Valsecchi, V.; Anzilotti, S.; Cuomo, O.; Vinciguerra, A.; Cepparulo, P.; Brancaccio, P.; Guida, N.; Blondeau, N.; Canzoniero, L. M. T.; Franco, C.; Amoroso, S.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283112
Citazioni:
Ionic homeostasis maintenance in ALS: Focus on new therapeutic targets / Sirabella, R., Valsecchi, V., Anzilotti, S., Cuomo, O., Vinciguerra, A., Cepparulo, P., Brancaccio, P., Guida, N., Blondeau, N., Canzoniero, L.M.T., Franco, C., Amoroso, S., Annunziato, L., Pignataro, G.. - In: FRONTIERS IN NEUROSCIENCE. - ISSN 1662-4548. - 12:AUG(2018), p. 510. [10.3389/fnins.2018.00510]
Abstract:
Amyotrophic lateral sclerosis (ALS) is one of the most threatening neurodegenerative disease since it causes muscular paralysis for the loss of Motor Neurons in the spinal cord, brainstem and motor cortex. Up until now, no effective pharmacological treatment is available. Two forms of ALS have been ...described so far: 90% of the cases presents the sporadic form (sALS) whereas the remaining 10% of the cases displays the familiar form (fALS). Approximately 20% of fALS is associated with inherited mutations in the Cu, Zn-superoxide dismutase 1 (SOD1) gene. In the last decade, ionic homeostasis dysregulation has been proposed as the main trigger of the pathological cascade that brings to motor-neurons loss. In the light of these premises, the present review will analyze the involvement in ALS pathophysiology of the most well studied metal ions, i.e., calcium, sodium, iron, copper and zinc, with particular focus to the role of ionic channels and transporters able to contribute in the regulation of ionic homeostasis, in order to propose new putative molecular targets for future therapeutic strategies to ameliorate the progression of this devastating neurodegenerative disease.
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Synergistic association of valproate and resveratrol reduces brain injury in ischemic stroke
Anno: 2018
Rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Autori/autrici: Faggi, L.; Pignataro, G.; Parrella, E.; Porrini, V.; Vinciguerra, A.; Cepparulo, P.; Cuomo, O.; Lanzillotta, A.; Mota, M.; Benarese, M.; Tonin, P.; Annunziato, L.; Spano, P.; Pizzi, M.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283124
Citazioni:
Synergistic association of valproate and resveratrol reduces brain injury in ischemic stroke / Faggi, L., Pignataro, G., Parrella, E., Porrini, V., Vinciguerra, A., Cepparulo, P., Cuomo, O., Lanzillotta, A., Mota, M., Benarese, M., Tonin, P., Annunziato, L., Spano, P., Pizzi, M.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 19:1(2018), p. 172. [10.3390/ijms19010172]
Abstract:
Histone deacetylation, together with altered acetylation of NF-κB/RelA, encompassing the K310 residue acetylation, occur during brain ischemia. By restoring the normal acetylation condition, we previously reported that sub-threshold doses of resveratrol and entinostat (MS-275), respectively, a...n activator of the AMP-activated kinase (AMPK)-sirtuin 1 pathway and an inhibitor of class I histone deacetylases (HDACs), synergistically elicited neuroprotection in a mouse model of ischemic stroke. To improve the translational power of this approach, we investigated the efficacy of MS-275 replacement with valproate, the antiepileptic drug also reported to be a class I HDAC blocker. In cortical neurons previously exposed to oxygen glucose deprivation (OGD), valproate elicited neuroprotection at 100 nmol/mL concentration when used alone and at 1 nmol/mL concentration when associated with resveratrol (3 nmol/mL). Resveratrol and valproate restored the acetylation of histone H3 (K9/18), and they reduced the RelA(K310) acetylation and the Bim level in neurons exposed to OGD. Chromatin immunoprecipitation analysis showed that the synergistic drug association impaired the RelA binding to the Bim promoter, as well as the promoter-specific H3 (K9/18) acetylation. In mice subjected to 60 min of middle cerebral artery occlusion (MCAO), the association of resveratrol 680 µg/kg and valproate 200 µg/kg significantly reduced the infarct volume as well as the neurological deficits. The present study suggests that valproate and resveratrol may represent a promising ready-to-use strategy to treat post-ischemic brain damage.
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Models and methods for conditioning the ischemic brain
Anno: 2018
Rivista: JOURNAL OF NEUROSCIENCE METHODS
Autori/autrici: Vinciguerra, A.; Cuomo, O.; Cepparulo, P.; Anzilotti, S.; Brancaccio, P.; Sirabella, R.; Guida, N.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283121
Citazioni:
Models and methods for conditioning the ischemic brain / Vinciguerra, A., Cuomo, O., Cepparulo, P., Anzilotti, S., Brancaccio, P., Sirabella, R., Guida, N., Annunziato, L., Pignataro, G.. - In: JOURNAL OF NEUROSCIENCE METHODS. - ISSN 0165-0270. - 310:(2018), pp. 63-74. [10.1016/j.jneumeth.2018.09.029]
Abstract:
Background: In the last decades the need to find new neuroprotective targets has addressed the researchers to investigate the endogenous molecular mechanisms that brain activates when exposed to a conditioning stimulus. Indeed, conditioning is an adaptive biological process activated by those interv...entions able to confer resistance to a deleterious brain event through the exposure to a sub-threshold insult. Specifically, preconditioning and postconditioning are realized when the conditioning stimulus is applied before or after, respectively, the harmul ischemia. Aims and Results: The present review will describe the most common methods to induce brain conditioning, with particular regards to surgical, physical exercise, temperature-induced and pharmacological approaches. It has been well recognized that when the subliminal stimulus is delivered after the ischemic insult, the achieved neuroprotection is comparable to that observed in models of ischemic preconditioning. In addition, subjecting the brain to both preconditioning as well as postconditioning did not cause greater protection than each treatment alone. Conclusions: The last decades have provided fascinating insights into the mechanisms and potential application of strategies to induce brain conditioning. Since the identification of intrinsic cell‐survival pathways should provide more direct opportunities for translational neuroprotection trials, an accurate examination of the different models of preconditioning and postconditioning is mandatory before starting any new project.
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Corrigendum to “NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia” (Neurobiology of Disease (2012) 45(1) (616–623)(S0969996111003391)(10.1016/j.nbd.2011.10.007))
Anno: 2017
Rivista: NEUROBIOLOGY OF DISEASE
Autori/autrici: Pignataro, G.; Boscia, F.; Esposito, E.; Sirabella, R.; Cuomo, O.; Vinciguerra, A.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283126
Citazioni:
Corrigendum to “NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia” (Neurobiology of Disease (2012) 45(1) (616–623)(S0969996111003391)(10.1016/j.nbd.2011.10.007)) / Pignataro, G., Boscia, F., Esposito, E., Sirabella, R., Cuomo, O., Vinciguerra, A., Di Renzo, G., Annunziato, L.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 98:(2017), pp. 160-161. [10.1016/j.nbd.2016.12.002]
Abstract:
The authors regret to report that an inadvertent error was noted in assembling Fig. 1. In particular, in this Figure were inserted data referring to control groups of another paper, authored by the same authors and appeared in J Cerebral Blood Flow and Metabolism (2011) 31, 352–370. This mista...ke was probably due to the fact that both Fig. 1 of the two manuscripts required the same control groups and were prepared and submitted at the same time. The data reported in the new Fig. 1 were obtained from the archive of the original films. The authors would like to apologise for any inconvenience caused.
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The expression and activity of KV3.4 channel subunits are precociously upregulated in astrocytes exposed to Aβ oligomers and in astrocytes of Alzheimer's disease Tg2576 mice
Anno: 2017
Rivista: NEUROBIOLOGY OF AGING
Autori/autrici: Boscia, F.; Pannaccione, A.; Ciccone, R.; Casamassa, A.; Franco, C.; Piccialli, I.; de Rosa, V.; Vinciguerra, A.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283111
Citazioni:
The expression and activity of KV3.4 channel subunits are precociously upregulated in astrocytes exposed to Aβ oligomers and in astrocytes of Alzheimer's disease Tg2576 mice / Boscia, F., Pannaccione, A., Ciccone, R., Casamassa, A., Franco, C., Piccialli, I., de Rosa, V., Vinciguerra, A., Di Renzo, G., Annunziato, L.. - In: NEUROBIOLOGY OF AGING. - ISSN 0197-4580. - 54:(2017), pp. 187-198. [10.1016/j.neurobiolaging.2017.03.008]
Abstract:
Astrocyte dysfunction emerges early in Alzheimer's disease (AD) and may contribute to its pathology and progression. Recently, the voltage gated potassium channel KV3.4 subunit, which underlies the fast-inactivating K+ currents, has been recognized to be relevant for AD pathogenesis and is emer...ging as a new target candidate for AD. In the present study, we investigated both in in vitro and in vivo models of AD the expression and functional activity of KV3.4 potassium channel subunits in astrocytes. In primary astrocytes our biochemical, immunohistochemical, and electrophysiological studies demonstrated a time-dependent upregulation of KV3.4 expression and functional activity after exposure to amyloid-β (Aβ) oligomers. Consistently, astrocytic KV3.4 expression was upregulated in the cerebral cortex, hippocampus, and cerebellum of 6-month-old Tg2576 mice. Further, confocal triple labeling studies revealed that in 6-month-old Tg2576 mice, KV3.4 was intensely coexpressed with Aβ in nonplaque associated astrocytes. Interestingly, in the cortical and hippocampal regions of 12-month-old Tg2576 mice, plaque-associated astrocytes much more intensely expressed KV3.4 subunits, but not Aβ. More important, we evidenced that the selective knockdown of KV3.4 expression significantly downregulated both glial fibrillary acidic protein levels and Aβ trimers in the brain of 6-month-old Tg2576 mice. Collectively, our results demonstrate that the expression and function of KV3.4 channel subunits are precociously upregulated in cultured astrocytes exposed to Aβ oligomers and in reactive astrocytes of AD Tg2576 mice.
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Imaging of brain TSPO expression in a mouse model of amyotrophic lateral sclerosis with 18F-DPA-714 and micro-PET/CT
Anno: 2016
Rivista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Autori/autrici: Gargiulo, S.; Anzilotti, S.; Coda, A. R. D.; Gramanzini, M.; Greco, A.; Panico, M.; Vinciguerra, A.; Zannetti, A.; Vicidomini, C.; Dolle, F.; Pignataro, G.; Quarantelli, M.; Annunziato, L.; Brunetti, A.; Salvatore, M.; Pappata, S.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283127
Citazioni:
Imaging of brain TSPO expression in a mouse model of amyotrophic lateral sclerosis with 18F-DPA-714 and micro-PET/CT / Gargiulo, S., Anzilotti, S., Coda, A.R.D., Gramanzini, M., Greco, A., Panico, M., Vinciguerra, A., Zannetti, A., Vicidomini, C., Dolle, F., Pignataro, G., Quarantelli, M., Annunziato, L., Brunetti, A., Salvatore, M., Pappata, S.. - In: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING. - ISSN 1619-7070. - 43:7(2016), pp. 1348-1359. [10.1007/s00259-016-3311-y]
Abstract:
Purpose: To evaluate the feasibility and sensitivity of 18F-DPA-714 for the study of microglial activation in the brain and spinal cord of transgenic SOD1G93A mice using high-resolution PET/CT and to evaluate the Iba1 and TSPO expression with immunohistochemistry. Methods: Nine symptomatic SOD1G93A ...mice (aged 117 ± 12.7 days, clinical score range 1 – 4) and five WT SOD1 control mice (aged 108 ± 28.5 days) underwent 18F-DPA-714 PET/CT. SUV ratios were calculated by normalizing the cerebellar (rCRB), brainstem (rBS), motor cortex (rMCX) and cervical spinal cord (rCSC) activities to that of the frontal association cortex. Two WT SOD1 and six symptomatic SOD1G93A mice were studied by immunohistochemistry. Results: In the symptomatic SOD1G93A mice, rCRB, rBS and rCSC were increased as compared to the values in WT SOD1 mice, with a statistically significantly difference in rBS (2.340 ± 0.784 vs 1.576 ± 0.287, p = 0.014). Immunofluorescence studies showed that TSPO expression was increased in the trigeminal, facial, ambiguus and hypoglossal nuclei, as well as in the spinal cord, of symptomatic SOD1G93A mice and was colocalized with increased Iba1 staining. Conclusion: Increased 18F-DPA-714 uptake can be detected with high-resolution PET/CT in the brainstem of transgenic SOD1G93A mice, a region known to be a site of degeneration and increased microglial activation in amyotrophic lateral sclerosis, in agreement with increased TSPO expression in the brainstem nuclei shown by immunostaining. Therefore, 18F-DPA-714 PET/CT might be a suitable tool to evaluate microglial activation in the SOD1G93A mouse model.
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Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt
Anno: 2016
Rivista: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Autori/autrici: Molinaro, P.; Sirabella, R.; Pignataro, G.; Petrozziello, T.; Secondo, A.; Boscia, F.; Vinciguerra, A.; Cuomo, O.; Philipson, K. D.; De Felice, M.; Di Lauro, R.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283129
Citazioni:
Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt / Molinaro, P., Sirabella, R., Pignataro, G., Petrozziello, T., Secondo, A., Boscia, F., Vinciguerra, A., Cuomo, O., Philipson, K.D., De Felice, M., Di Lauro, R., Di Renzo, G., Annunziato, L.. - In: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM. - ISSN 0271-678X. - 36:10(2016), pp. 1790-1803. [10.1177/0271678X15611913]
Abstract:
Three different Na+/Ca2+ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are expressed in brain where they play a relevant role in maintaining Na+and Ca2+ homeostasis. Although the neuroprotective roles of NCX2 and NCX3 in stroke have been elucidated, the relevance of NCX1 is still unknown because o...f embryonic lethality of its knocking-out, heart dysfunctions when it is overexpressed, and the lack of selectivity in currently available drugs. To overcome these limitations we generated two conditional genetically modified mice that upon tamoxifen administration showed a selective decrease or increase of NCX1 in cortical and hippocampal neurons. Interestingly, in cortex and hippocampus NCX1 overexpression increased, where NCX1 knock-out reduced, both exchanger activity and Akt1 phosphorylation, a neuronal survival signaling. More important, mice overexpressing NCX1 showed a reduced ischemic volume and an amelioration of focal and general deficits when subjected to transient middle cerebral artery occlusion. Conversely, NCX1-knock-out mice displayed a worsening of brain damage, focal and neurological deficits with a decrease in Akt phosphorylation. These results support the idea that NCX1 overexpression/activation may represent a feasible therapeutic opportunity in stroke intervention.
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NCX1 Exchanger Cooperates with Calretinin to Confer Preconditioning-Induced Tolerance Against Cerebral Ischemia in the Striatum
Anno: 2016
Rivista: MOLECULAR NEUROBIOLOGY
Autori/autrici: Boscia, F.; Casamassa, A.; Secondo, A.; Esposito, A.; Pannaccione, A.; Sirabella, R.; Pignataro, G.; Cuomo, O.; Vinciguerra, A.; de Rosa, V.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283119
Citazioni:
NCX1 Exchanger Cooperates with Calretinin to Confer Preconditioning-Induced Tolerance Against Cerebral Ischemia in the Striatum / Boscia, F., Casamassa, A., Secondo, A., Esposito, A., Pannaccione, A., Sirabella, R., Pignataro, G., Cuomo, O., Vinciguerra, A., de Rosa, V., Annunziato, L.. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - 53:2(2016), pp. 1365-1376. [10.1007/s12035-015-9095-4]
Abstract:
Recently, the Na+/Ca+2 exchanger NCX1 and the calcium binding protein calretinin have emerged as new molecular effectors of delayed preconditioning in the brain. In the present study, we investigated whether NCX1 and calretinin cooperate within the preconditioned striatum to confer neurons greater r...esistance to degeneration. Confocal microscopy analysis revealed that NCX1 expression was upregulated in calretinin-positive interneurons in the rat striatum after tolerance induction. Consistently, coimmunoprecipitation assays performed on human SHSY-5Y cells, a neuronal cell line which constitutively expresses calretinin, revealed a binding between NCX1 and calretinin. Finally, silencing of calretinin expression, both in vitro and in vivo, significantly prevented preconditioning-induced neuroprotection. Interestingly, our biochemical and functional studies showed that the selective silencing of calretinin in brain cells significantly prevented not only the preconditioning-induced upregulation of NCX1 expression and activity but also the activation of the prosurvival protein kinase Akt, which is involved in calretinin and NCX1 protective actions. Collectively, our results indicate that the Na+/Ca+2 exchanger NCX1 and the calcium binding protein calretinin cooperate within the striatum to confer tolerance against cerebral ischemia.
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Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by Epigenetic mechanism
Anno: 2015
Rivista: THE JOURNAL OF NEUROSCIENCE
Autori/autrici: Formisano, L.; Guida, N.; Valsecchi, V.; Cantile, M.; Cuomo, O.; Vinciguerra, A.; Laudati, G.; Pignataro, G.; Sirabella, R.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283116
Citazioni:
Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by Epigenetic mechanism / Formisano, L., Guida, N., Valsecchi, V., Cantile, M., Cuomo, O., Vinciguerra, A., Laudati, G., Pignataro, G., Sirabella, R., Di Renzo, G., Annunziato, L.. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - 35:19(2015), pp. 7332-7348. [10.1523/JNEUROSCI.2174-14.2015]
Abstract:
The Na+-Ca2+ exchanger 1 (NCX1) is reduced in stroke by the RE1-silencing transcription factor (REST), whereas it is increased in ischemic brain preconditioning (PC) by hypoxia-inducible factor 1 (HIF-1). Because ncx1 brain promoter (ncx1-Br) has five putative consensus sequences, named Sp1A–E..., for the specificity protein (Sp) family of transcription factors (Sp1–4), we investigated the role of this family in regulating ncx1 transcription in rat cortical neurons. Here we found that Sp1 is a transcriptional activator, whereas Sp3 is a transcriptional repressor of ncx1, and that both bind ncx1-Br in a sequence-specific manner, modulating ncx1 transcription through the Sp1 sites C–E. Furthermore, by transient middle cerebral artery occlusion (tMCAO) in rats, the transcriptional repressors Sp3 and REST colocalized with the two histone-deacetylases (HDACs) HDAC1 and HDAC2 on the ncx1-Br, with a consequent hypoacetylation. Contrarily, in PC+tMCAO the transcriptional activators Sp1 and HIF-1 colocalized with histone acetyltransferase p300 on ncx1-Br with a consequent hyperacetylation. In addition, in neurons silenced with siRNA of NCX1 and subjected to oxygen and glucose deprivation (OGD) (3 h) plus reoxygenation (RX) (24 h), the neuroprotection of Class I HDAC inhibitor MS-275 was counteracted, whereas in neurons overexpressing NCX1 and subjected to ischemic preconditioning (PC+OGD/RX), the neurotoxic effect of p300 inhibitor C646 was prevented. Collectively, these results demonstrate that NCX1 expression is regulated by the Sp3/REST/HDAC1/HDAC2 complex in tMCAO and by the Sp1/HIF-1/p300 complex in PC+tMCAO and that epigenetic intervention, by modulating the acetylation of ncx1-Br, may be a strategy for the development of innovative therapeutic intervention in stroke.
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Ionic homeostasis in brain conditioning
Anno: 2015
Rivista: FRONTIERS IN NEUROSCIENCE
Autori/autrici: Cuomo, O.; Vinciguerra, A.; Cerullo, P.; Anzilotti, S.; Brancaccio, P.; Bilo, L.; Scorziello, A.; Molinaro, P.; Di Renzo, G.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283114
Citazioni:
Ionic homeostasis in brain conditioning / Cuomo, O., Vinciguerra, A., Cerullo, P., Anzilotti, S., Brancaccio, P., Bilo, L., Scorziello, A., Molinaro, P., Di Renzo, G., Pignataro, G.. - In: FRONTIERS IN NEUROSCIENCE. - ISSN 1662-4548. - 9:JUL(2015), p. 277. [10.3389/fnins.2015.00277]
Abstract:
Most of the research aimed at identifying new stroke therapies focuses on strategies which induce, mimic, or boost endogenous protective responses. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolera...nce in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1-3 days. A new promising approach for neuroprotection derives from postconditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and postconditioning. Although the mechanisms are not yet fully understood, recent evidence highlights the preminent role of the ionic homeostasis maintenance. The present article will review the role of ionic transporters and channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and postconditioning in adult brain, with particular regards to Na+/Ca2+ exchangers (NCXs), plasma membrane Ca2+-ATPase (PMCA), Na+/H+ exchanger (NHE), Na+/K+/2Cl- cotransport (NKCC) and acid-sensing ionic channels (ASIC).
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Neuroprotective Effect of VEGF-Mimetic Peptide QK in Experimental Brain Ischemia Induced in Rat by Middle Cerebral Artery Occlusion
Anno: 2015
Rivista: ACS CHEMICAL NEUROSCIENCE
Autori/autrici: Pignataro, G.; Ziaco, B.; Tortiglione, A.; Gala, R.; Cuomo, O.; Vinciguerra, A.; Lapi, D.; Mastantuono, T.; Anzilotti, S.; D'Andrea, L. D.; Pedone, C.; Di Renzo, G.; Annunziato, L.; Cataldi, M.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283123
Citazioni:
Neuroprotective Effect of VEGF-Mimetic Peptide QK in Experimental Brain Ischemia Induced in Rat by Middle Cerebral Artery Occlusion / Pignataro, G., Ziaco, B., Tortiglione, A., Gala, R., Cuomo, O., Vinciguerra, A., Lapi, D., Mastantuono, T., Anzilotti, S., D'Andrea, L.D., Pedone, C., Di Renzo, G., Annunziato, L., Cataldi, M.. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 6:9(2015), pp. 1517-1525. [10.1021/acschemneuro.5b00175]
Abstract:
We investigated the effect of the VEGF-mimetic peptide, QK, on ischemic brain damage and on blood-brain barrier permeability in the rat. QK administered by the intracerebroventricular, intravenous, or intranasal route caused a 40% decrease in ischemic brain damage induced by permanent occlusion of t...he middle cerebral artery relative to that in controls. No increase in the volume of the ischemic hemisphere compared to that of the contralateral nonischemic hemisphere was observed in rats treated with QK, suggesting that this peptide did not cause brain edema. The effect of QK on vessel permeability was evaluated by intravital pial microvessel videoimaging, a technique that allows the pial vessels to be visualized through a surgically prepared open cranial window. The results showed that QK did not cause any leakage of intravenously injected fluorescein-dextran conjugates after intracarotid administration or topical application to the brain cortex. Collectively, these data suggest that QK may exert neuroprotective activity in the context of stroke without promoting any increase in vascular permeability. Because VEGF's neuroprotective activity may be overshadowed by the appearance of brain edema and microbleeds, QK could represent a significant step forward in stroke treatment.
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MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits
Anno: 2014
Rivista: MOLECULAR THERAPY
Autori/autrici: Vinciguerra, A.; Formisano, L.; Cerullo, P.; Guida, N.; Cuomo, O.; Esposito, A.; Di Renzo, G.; Annunziato, L.; Pignataro, G.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283115
Citazioni:
MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits / Vinciguerra, A., Formisano, L., Cerullo, P., Guida, N., Cuomo, O., Esposito, A., Di Renzo, G., Annunziato, L., Pignataro, G.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 22:10(2014), pp. 1829-1838. [10.1038/mt.2014.113]
Abstract:
Na + /Ca2+ exchanger (NCX) is a plasma membrane transporter that, by regulating Ca2+ and Na + homeostasis, contributes to brain stroke damage. The objectives of this study were to investigate whether there might be miRNAs in the brain able to regulate NCX1 expression and, thereafter, to set up a val...id therapeutic strategy able to reduce stroke-induced brain damage by regulating NCX1 expression. Thus, we tested whether miR-103-1, a microRNA belonging to the miR-103/107 family that on the basis of sequence analysis might be a potential NCX1 regulator, could control NCX1 expression. The role of miR-103-1 was assessed in a rat model of transient cerebral ischemia by evaluating the effect of the correspondent antimiRNA on both brain infarct volume and neurological deficits. NCX1 expression was dramatically reduced when cortical neurons were exposed to miR-103-1. This alleged tight regulation of NCX1 by miR-103-1 was further corroborated by luciferase assay. Notably, antimiR-103-1 prevented NCX1 protein downregulation induced by the increase in miR-103-1 after brain ischemia, thereby reducing brain damage and neurological deficits. Overall, the identification of a microRNA able to selectively regulate NCX1 in the brain clarifies a new important molecular mechanism of NCX1 regulation in the brain and offers the opportunity to develop a new therapeutic strategy for stroke.
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Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype
Anno: 2014
Rivista: CELL DEATH & DISEASE
Autori/autrici: Cantarella, G.; Pignataro, G.; Di Benedetto, G.; Anzilotti, S.; Vinciguerra, A.; Cuomo, O.; Di Renzo, G. F.; Parenti, C.; Annunziato, L.; Bernardini, R.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283113
Citazioni:
Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype / Cantarella, G., Pignataro, G., Di Benedetto, G., Anzilotti, S., Vinciguerra, A., Cuomo, O., Di Renzo, G.F., Parenti, C., Annunziato, L., Bernardini, R.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 5:7(2014), pp. e1331-e1331. [10.1038/cddis.2014.286]
Abstract:
TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved in the induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. As... ischemic preconditioning reduces inflammatory response to brain ischemia and ameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke and ischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achieve this aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middle cerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia was preceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors and downregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on the mechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new molecular targets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the death receptors, or to activate the decoy receptors open new perspectives for the treatment of stroke. © 2014 Macmillan Publishers Limited All rights reserved 2041-4889/14.
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Conjunctival instillation of plasminogen eliminates ocular lesion in B6.129P2-Plgtm1Jld transgenic mice, a model of ligneous conjunctivitis
Anno: 2013
Rivista: PHARMACOLOGICAL RESEARCH
Autori/autrici: Pignataro, G.; Vinciguerra, A.; Cuomo, O.; Sirabella, R.; Di Renzo, G. F.; Scorziello, A.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283122
Citazioni:
Conjunctival instillation of plasminogen eliminates ocular lesion in B6.129P2-Plgtm1Jld transgenic mice, a model of ligneous conjunctivitis / Pignataro, G., Vinciguerra, A., Cuomo, O., Sirabella, R., Di Renzo, G.F., Scorziello, A.. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 74:(2013), pp. 45-48. [10.1016/j.phrs.2013.04.012]
Abstract:
Ligneous conjunctivitis is a severe and rare chronic "idiopathic membraneous" conjunctivitis, characterized by the formation of pseudomembranes mostly on the palpebral surfaces that progressively replace the normal mucosa. Evidence has been provided that ligneous conjunctivitis is caused b...y a severe systemic plasminogen deficiency with decreased plasminogen antigen and decreased plasminogen functional activities. Objective of the present study is to verify the hypothesis that a topical eye application of plasminogen is able to ameliorate the consequences of this disease. Here we report the results of pre-clinical studies performed to investigate the therapeutic effectiveness of an eye-drop plasminogen preparation in B6.129P2-Plgtm1Jld transgenic mice, a model of ligneous conjunctivitis. The entity of protection mediated by plasminogen was evaluated by measuring the extent of the eye lesion by means of a computerized system and dedicated software. The results of the present study clearly showed that the administration for six times a day of plasminogen eye-drop solution in the lesioned eye of animals knock-out for plasminogen gene and developing ligneous conjunctivitis caused a dose and time related reduction of the extent of the ocular lesion. These findings may pave the road for the pharmacological treatment of the ocular lesion associated to the ligneous conjunctivitis that at the present is surgically treated by removing the pseudomembranes generated on the eye. © 2013 Elsevier Ltd. All right reserved.
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NCX1 is a new rest target gene: Role in cerebral ischemia
Anno: 2013
Rivista: NEUROBIOLOGY OF DISEASE
Autori/autrici: Formisano, L.; Guida, N.; Valsecchi, V.; Pignataro, G.; Vinciguerra, A.; Pannaccione, A.; Secondo, A.; Boscia, F.; Molinaro, P.; Sisalli, M. J.; Sirabella, R.; Casamassa, A.; Canzoniero, L. M. T.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283118
Citazioni:
NCX1 is a new rest target gene: Role in cerebral ischemia / Formisano, L., Guida, N., Valsecchi, V., Pignataro, G., Vinciguerra, A., Pannaccione, A., Secondo, A., Boscia, F., Molinaro, P., Sisalli, M.J., Sirabella, R., Casamassa, A., Canzoniero, L.M.T., Di Renzo, G., Annunziato, L.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 50:1(2013), pp. 76-85. [10.1016/j.nbd.2012.10.010]
Abstract:
The Na+-Ca2+ exchanger 1 (NCX1), a bidirectional transporter that mediates the electrogenic exchange of one calcium ion for three sodium ions across the plasmamembrane, is known to be involved in brain ischemia. Since the RE1-silencing transcription factor (REST) is a key modulator of neuronal gene ...expression in several neurological conditions, we studied the possible involvement of REST in regulating NCX1 gene expression and activity in stroke. We found that: (1) REST binds in a sequence specific manner and represses through H4 deacetylation, ncx1 gene in neuronal cells by recruting CoREST, but not mSin3A. (2)In neurons and in SH-SY5Y cells REST silencing by siRNA and site-direct mutagenesis of REST consensus sequence on NCX1 brain promoter determined an increase in NCX1 promoter activity. (3)By contrast, REST overexpression caused a reduction in NCX1 protein expression and activity. (4)Interestingly, in rats subjected to transient middle cerebral artery occlusion (tMCAO) and in organotypic hippocampal slices or SH-SY5Y cells exposed to oxygen and glucose deprivation (OGD) plus reoxygenation (RX), the increase in REST was associated with a decrease in NCX1. However, this reduction was reverted by REST silencing. (5)REST knocking down, along with the deriving NCX1overexpression in the deep V and VIb cortical layers caused a marked reduction in infarct volume after tMCAO. Double silencing of REST and NCX1 completely abolished neuroprotection induced by siREST administration.Collectively, these results demonstrate that REST, by regulating NCX1 expression, may represent a potential druggable target for the treatment of brain ischemia. © 2012 Elsevier Inc.
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Surgical methods to induce brain preconditioning
Anno: 2013
Autori/autrici: Pignataro, G.; Cuomo, O.; Vinciguerra, A.
Lingua: ENG
Classificazione IRIS: 2.1 Contributo in volume (Capitolo o Saggio)
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283128
Citazioni:
Surgical methods to induce brain preconditioning / Pignataro, G., Cuomo, O., Vinciguerra, A.. - (2013), pp. 225-240. [10.1007/978-1-4419-9695-4_10]

NNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion
Anno: 2013
Rivista: NEUROBIOLOGY OF DISEASE
Autori/autrici: Pignataro, G.; Esposito, E.; Sirabella, R.; Vinciguerra, A.; Cuomo, O.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283117
Citazioni:
NNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion / Pignataro, G., Esposito, E., Sirabella, R., Vinciguerra, A., Cuomo, O., Di Renzo, G., Annunziato, L.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 54:(2013), pp. 105-114. [10.1016/j.nbd.2013.02.008]
Abstract:
It has recently been hypothesized that a sub-lethal ischemic insult induced in one organ is able to protect from a harmful ischemia occurring in a different organ. The objective of this study is to identify new putative mechanisms of neuroprotection elicited by remote ischemic femoral postconditioni...ng. A 50% reduction in the infarct volume was observed when 100. min of middle cerebral artery occlusion was followed, 10. min later, by the remote postconditioning stimulus represented by 20. min of femoral artery occlusion. The use of in vivo silencing strategy allowed to demonstrate that NO production through nNOS mediates part of the neuroprotection. Indeed, whereas CNS nNOS expression was up-regulated by remote postconditioning, the pharmacological inhibition of nNOS or its silencing-mediated knocking-down partially prevented this neuroprotective effect. This nNOS overexpression seemed to be p-ERK dependent. In fact, p-ERK expression increased in brain cortex after remote postconditioning, and its pharmacological inhibition prevented both nNOS overexpression and remote postconditioning-mediated neuroprotection. Interestingly, neuroprotection induced by remote postconditioning was partially prevented when ganglion transmission was pharmacologically interrupted by hexamethonium, thus showing that neural factors are involved in this phenomenon.Collectively, the present study demonstrates that p-ERK and nNOS take part to the complex cascade of events triggered by ischemic remote postconditioning. © 2013 Elsevier Inc.
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The antiepileptic drug levetiracetam suppresses non-convulsive seizure activity and reduces ischemic brain damage in rats subjected to permanent middle cerebral artery occlusion
Anno: 2013
Rivista: PLOS ONE
Autori/autrici: Cuomo, O.; Rispoli, V.; Leo, A.; Politi, G. B.; Vinciguerra, A.; Di Renzo, G.; Cataldi, M.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283120
Citazioni:
The antiepileptic drug levetiracetam suppresses non-convulsive seizure activity and reduces ischemic brain damage in rats subjected to permanent middle cerebral artery occlusion / Cuomo, O., Rispoli, V., Leo, A., Politi, G.B., Vinciguerra, A., Di Renzo, G., Cataldi, M.. - In: PLOS ONE. - ISSN 1932-6203. - 8:11(2013), p. e80852. [10.1371/journal.pone.0080852]
Abstract:
The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting ep...ileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug. © 2013 Cuomo et al.
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NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia
Anno: 2012
Rivista: NEUROBIOLOGY OF DISEASE
Autori/autrici: Pignataro, G.; Boscia, F.; Esposito, E.; Sirabella, R.; Cuomo, O.; Vinciguerra, A.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283109
Citazioni:
NCX1 and NCX3: Two new effectors of delayed preconditioning in brain ischemia / Pignataro, G., Boscia, F., Esposito, E., Sirabella, R., Cuomo, O., Vinciguerra, A., Di Renzo, G., Annunziato, L.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 45:1(2012), pp. 616-623. [10.1016/j.nbd.2011.10.007]
Abstract:
Substantial evidence has established that a short sub-lethal brain ischemia applied before a prolonged harmful ischemic episode confers ischemic neuroprotection, a phenomenon named ischemic preconditioning. Na+/Ca2+ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasmamembrane ionic transporter...s widely distributed in the brain, where they are involved in the control of Na+ and Ca2+ homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the preconditioning-induced neuroprotection. NCX protein expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to ischemia alone, to ischemic preconditioning alone, or to ischemic preconditioning plus ischemia. NCX1 and NCX3 were up-regulated in those brain regions protected by preconditioning treatment. These changes were mediated by p-AKT, since the p-AKT inhibition prevented the up-regulation of both isoforms. The relevant role of NCX1 and NCX3 during preconditioning was further confirmed when NCX1 and NCX3 silencing, induced by icv infusion of siRNA, partially reverted the preconditioning-induced neuroprotection. The enhancement of NCX1 and NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke. © 2011 Elsevier Inc..
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Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: Current and emerging therapeutic options
Anno: 2011
Rivista: CURRENT OPINION IN PHARMACOLOGY
Autori/autrici: Pignataro, G.; Capone, D.; Polichetti, G.; Vinciguerra, A.; Gentile, A.; Di Renzo, G.; Annunziato, L.
Lingua: ENG
Classificazione IRIS: 1.1 Articolo in rivista
Scheda completa IRIS: https://iris.univpm.it/handle/11566/283125
Citazioni:
Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: Current and emerging therapeutic options / Pignataro, G., Capone, D., Polichetti, G., Vinciguerra, A., Gentile, A., Di Renzo, G., Annunziato, L.. - In: CURRENT OPINION IN PHARMACOLOGY. - ISSN 1471-4892. - 11:4(2011), pp. 378-394. [10.1016/j.coph.2011.05.003]
Abstract:
The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processe...s accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes. It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immunosuppressant effects, are provided with neuroprotective properties. In fact, mTOR is involved in the mechanism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis. © 2011 Elsevier Ltd. All rights reserved.
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