molecular mechanisms of NCX1 and NCX3-induced neuroprotection in anoxic brain preconditionoing

sisalli, maria josè (2011) molecular mechanisms of NCX1 and NCX3-induced neuroprotection in anoxic brain preconditionoing. [Tesi di dottorato] (Inedito)

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Abstract

Ischemic preconditioning (IPC) represents an important adaptation mechanism of CNS, which results in its increased tolerance to the lethal cerebral ischemia. The molecular mechanisms responsible for the induction and maintenance of ischemic tolerance in the brain are complex and remain undefined. As the expression of the three isoforms of the sodium calcium exchanger (NCX), NCX1, NCX2 and NCX3, was reduced during cerebral ischemia and considering the relevance of nitric oxide (NO) in the IPC modulation, we investigated the functional relationship between NO and NCXs in the regulation of Ca2+ homeostasis, as molecular mechanism responsible for ischemic tolerance. To this aim we set up an in vitro model of Ischemic preconditioning by exposing cortical neurons to a 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3hrs OGD followed by reoxygenation (lethal insult). IPC was able to stimulate NCX activity, an effect blocked by L-NAME and siRNA against NCX1 and NCX3 treatment thus suggesting that NCX1 and NCX3 play a pivotal role in the modulation of calcium homeostasis during IPC in a NO-dependent manner. Interestingly, IPC-induced NCX1 increased activity contributes to ER refilling by counteracting ER stress described in OGD/Reoxygenation. Conversely, NCX3 increased activity promotes mitochondrial calcium handling and improves mitochondrial function during OGD/Reoxygenation. Finally, as concern cell viability our data showed that both siNCX1 and siNCX3 prevented the neuroprotection exerted by IPC in rat cortical neurons exposed to OGD/Reoxygenation. Collectively, these results suggest a possible involvement of NCX1 and NCX3 in the crosstalk between ER and mitochondria as novel mechanism for IPC-induced neuroprotection.

Tipologia di documento:Tesi di dottorato
Parole chiave:cerebral ischemic preconditioning, sodium/calcium exchanger, intracellular calcium homeostasis
Settori scientifico-disciplinari MIUR:Area 05 Scienze biologiche > BIO/14 FARMACOLOGIA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Annunziato, Luciolannunzi@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Di Renzo, Gianfranco
Stato del full text:Inedito
Data:30 Novembre 2011
Numero di pagine:142
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Neuroscienze
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Neuroscienze
Ciclo di dottorato:24
Numero di sistema:8814
Depositato il:07 Dicembre 2011 11:50
Ultima modifica:23 Aprile 2012 11:51

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