Why have Ionotropic andMetabotropic Glutamate Antagonists Failed in Stroke Therapy?
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چکیده
The concept of ‘‘excitotoxicity’’ was introduced in 1969 when Olney and Sharpe first demonstrated that neurons exposed to their own neurotransmitter glutamate were destined to die [49]. Later on, in 1985, glutamate toxicity was associated with anoxic cell death, since anoxic depolarization resulted in the release of glutamate into the extracellular compartments [42, 54]. Similarly, in 1987, Choi indicated that glutamate was a remarkably potent and rapidly acting neurotoxin able to mediate neurotoxic effects by inducing Ca2þ influx through glutamate receptor activation, and he supported the theory that glutamate can be considered a key neurotransmitter in developing many neurological diseases [13, 14, 15]. Since then, glutamate receptors have been themost studied channels involved in ischemic stroke pathophysiology. Glutamate can exert its effects by interacting with both ionotropic glutamate receptors (iGluRs), also referred to as ligand-gated ion channels, and metabotropic glutamate G-protein-coupled receptors. The group of iGluRs comprises three major classes, the a-amino-3hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, kainate (KA) receptors, and N-methyl-D-aspartate (NMDA) receptors, named according to their selective agonists [62]. Glutamatergic synapses frequently harbor both AMPA and NMDA receptors. Characteristically, both classes of receptors differ in their response kinetics upon presynaptic glutamate release. Indeed, AMPA receptors mediate fast glutamate-gated postsynaptic responses, even at very negative potentials or in the absence of action potentials. The fast desensitization of AMPA receptors leads to short excitatory postsynaptic currents (EPSCs). In contrast, NMDA receptors contain an agonist-binding site, i.e., a glycine modulatory site, and other binding sites within the ion channel, where magnesium exerts a voltage-dependent block [21]. Acting as detectors of
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