AMPAergic mechanisms linked to cerebral ischemia

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Brain ischemia is a major cause of death and the most common element of disability in the adult population worldwide. This phenomenon occurs when blood flow is reduced or interrupted in the various brain districts leading to oxygen and glucose deprivation (OGD), which by triggering a complex series of biochemical plus molecular mechanisms such as an exacerbated production of misfolded and oxidized proteins together with the breakdown of cellular integrity are responsible for neuronal cell death. Despite the mechanisms that underlie the triggering of ischemic insults are still unclear, numerous studies are pointing to excitotoxic glutamatergic neuronal signaling processes as key mediators of these events. Indeed, cultured neurons deriving from global cerebral ischemia appear to respond to OGD with a rapid internalization of α ‑ amino ‑ 3 ‑ hydroxy ‑ 5 ‑ methyl ‑ 4 ‑ isoxazolepropionic acid receptors (AMPAR) thereby suggesting them as critical components of OGD-induced cell death. It strongly seems that OGD-dependent neuronal ischemia occurs via GluR2-sites in which a switching from GluR2-containing Ca 2+ -impermeable receptors to GluR2-lacking Ca 2+ -permeable subtypes constitutes an important step. Interestingly attention regarding excitotoxicity-related ischemic events, aside being largely directed to the o veractivation of AMPARs, appear to be also tightly linked to the translocation of the pro-apoptotic protein Bax to the mitochondria accounting for the activation of the caspase factors. Although the brain is able to repair part of the neuronal damages and to restore the morpho-functional organization, cerebral ischemia more than ever continues to attract much attention especially due to its elevated mortality feature. In this review we analyzed the role played by GluR2 AMPAR subunit in the pathological processes that lead to neurodegenerative diseases with particular attention being paid to the assembly of the major synaptic AMPARs together with cellular events that feasibly account for ischemic brain damages. In this context, knowledge of the different molecular mechanisms operating under these conditions may surely provide helpful indications regarding the identification of new therapeutic targets for treating cerebral ischemia.