ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia.
Over the last few years, although extensive studies have focused on the relevant function played by the sodium-calcium exchanger (NCX) during focal ischemia, a thorough understanding of its role still remains a controversial issue. We explored the consequences of the pharmacological inhibition of this antiporter with conventional pharmacological approach, with the synthetic inhibitory peptide, XIP, or with an antisense strategy on the extent of brain damage induced by the permanent occlusion of middle cerebral artery (pMCAO) in rats. Collectively, the results of these studies suggest that ncx1 and ncx3 genes could be play a major role to limit the severity of ischemic damage probably as they act to dampen [Na+]i and [Ca2+]i overload. This mechanism seems to be normally activated in the ischemic brain as we found a selective upregulation of NCX1 and NCX3 mRNA levels in regions of the brain surviving to an ischemic insult. Despite this transcript increase, NCX1, NCX2, and NCX3 proteins undergo an extensive proteolytic degradation in the ipsilateral cerebral hemisphere. All together these results suggest that a rescue program centered on an increase NCX function and expression could halt the progression of the ischemic damage. On the basis of this evidence we directed our attention to the understanding of the transductional and transcriptional pathways responsible for NCX upregulation. To this aim, we are studying whether the brain isoform of Akt, Akt1, which is a downstream effector of neurotrophic factors, such as NGF can, in addition to affecting the other prosurvival cascades, also exert its neuroprotective effect by modulating the expression and activity of ncx1, ncx2, and ncx3 gene products.
Annunziato
L
L
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, via Sergio Pansini 5, 80131 Naples, Italy. lannunzi@unina.it
Pignataro
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Boscia
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Sirabella
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Formisano
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Saggese
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Cuomo
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Gala
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Secondo
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A
Viggiano
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Molinaro
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Valsecchi
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V
Tortiglione
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Adornetto
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Scorziello
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Cataldi
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Di Renzo
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D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D015687:Cell Hypoxia; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000235:genetics*
D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger