It is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na+ ([Na+]i) and Ca2+ ([Ca2+]i) ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na+]i increase is attributable to both cell swelling and microtubular disorganization—2 phenomena that lead to cell necrosis1—a change in [Ca2+]i has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, and protease activation. Since Olney’s seminal work firstly suggested that excitatory aminoacids could elicit neurotoxicity,2 a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca2+ and Na+ ions into neurons through ionotropic glutamate receptor subtypes. In the last 3 years, several seminal experimental works are markedly changing the scenario in this field. In fact, it has been shown that some integral plasma-membrane proteins, involved in the control of Ca2+ and Na+ ion influx or efflux and, therefore, responsible for maintaining the homeostasis of these 2 cations, might function as crucial players in the brain ischemic process. Indeed, these proteins, by regulating Na+ and Ca2+ homeostasis, may provide the molecular basis underlying glutamate-independent Ca2+ overload mechanisms in neuronal ischemic cell death and, most important, may represent more suitable molecular targets for therapeutic intervention. Here we discuss the role of ASICs, TRPM7 channels and NCX in the pathogenesis of brain ischemic damage.

Glutamate-independent calcium toxicity: Introduction.

ANNUNZIATO, LUCIO;CATALDI, MAURO;PIGNATARO, GIUSEPPE;SECONDO, AGNESE;
2007

Abstract

It is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na+ ([Na+]i) and Ca2+ ([Ca2+]i) ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na+]i increase is attributable to both cell swelling and microtubular disorganization—2 phenomena that lead to cell necrosis1—a change in [Ca2+]i has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, and protease activation. Since Olney’s seminal work firstly suggested that excitatory aminoacids could elicit neurotoxicity,2 a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca2+ and Na+ ions into neurons through ionotropic glutamate receptor subtypes. In the last 3 years, several seminal experimental works are markedly changing the scenario in this field. In fact, it has been shown that some integral plasma-membrane proteins, involved in the control of Ca2+ and Na+ ion influx or efflux and, therefore, responsible for maintaining the homeostasis of these 2 cations, might function as crucial players in the brain ischemic process. Indeed, these proteins, by regulating Na+ and Ca2+ homeostasis, may provide the molecular basis underlying glutamate-independent Ca2+ overload mechanisms in neuronal ischemic cell death and, most important, may represent more suitable molecular targets for therapeutic intervention. Here we discuss the role of ASICs, TRPM7 channels and NCX in the pathogenesis of brain ischemic damage.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/202660
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 19
social impact