Page - (000182) - in Biomedical Chemistry: Current Trends and Developments

potentials. After ischemia, the inhibition of ATP synthesis by mitochondria leads to a rapid ATP consumption, which causes a neuronal membrane depolarization with the release of K+ and Na+ entry into cells (Caplan, 2009). Energy failure also impedes the plasma membrane Ca2+ ATPase to maintain the very low calcium concentrations usually found within the cells (Doyle, 2008). This, together with the activation of voltage-dependent calcium channels, leads to the release of neurotransmitters, especially glutamate, which plays a critical role in the ischemic damage (Nicholls, 1990; Brouns, 2009). A large concentration gradient of glutamate is maintained across the plasma membrane by sodium-dependent glutamate transporters located at the plasma membrane, which maintain a high cytosolic glutamate concentration (approximately 10 mM) when compared to the synaptic concentration (in the micromolar range) (Hsu, 1998). Membrane depolarization during ischemia also induces a reversal of glutamate uptake carriers and enables glutamate to exit the cells along its concentration gradient, further increasing its accumulation in the extracellular space (Nicholls, 1990; Rossi, 2000). The extracellular accumulation of glutamate leads to excitotoxic stimulation of synaptic and extra-synaptic ionotropic and metabotropic glutamate receptors, which will result in neuronal dysfunction and death (Choi, 1988; Sims, 1995; Kroemer, 2009). In particular, the stimulation of AMPA and NMDA receptors causes an influx of Na+, and NMDA receptors are also characterized by a high Ca2+ permeability and conductance properties (Dong, 2009). Activation of group I mGluR receptors, which includes mGluR1 and mGluR5, increases the intracellular inositol trisphospate (IP3), thereby activating protein kinase C and releasing Ca2+ from neuronal stores (Pin, 2002; Friedman, 2006). Therefore, overactivation of NMDA receptors and mGluR contribute to a [Ca2+]i overload. AMPA receptors are not normally calcium permeable due to the GluA2 subunit, but the downregulation of this subunit after ischemia increases the calcium permeability of these receptors, and thus allows AMPA receptors to contribute to delayed cell death (Liu, 2006; Peng, 2006). Glutamatergic signaling and excitotoxic mechanisms play a role in chronic neurodegenerative disorders. Alzheimer’s Disease is characterized by 3 neuropathological hallmarks: deposits of amyloid