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Abstract
Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters (kalia et al., 2008).
There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA) , -amino -3-hydroxy -5-methyl -4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein–coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain.
Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors can result in excitotoxicity (glutamate-related cell injury or death) and may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer disease, multiple sclerosis and Huntington’s disease. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits, yet the usefulness of most drugs was limited by their actions on normal synaptic transmission or by additional side effects.
However, there are a handful of drugs that have been used in clinical neurology for many years only later to be discovered to target the NMDAR-glutamate system, suggesting there is a role for NMDAR-based treatments for some neurological disorders. This role is supported by the modest benefit of the NMDAR antagonist memantine in the treatment of Alzheimer’s disease. The repertoire of NMDAR-targeted drugs in neurology is expected to grow in the near future.
We also reviewed the role of non-NMDA receptors and glutamate transporters in the pathogenesis of various neurological diseases that could be a future therapeutic targets for drug therapy as many agents proved effectiveness in animal models .
The glutamate system is the most complex of all neurotransmitter systems in the CNS, with the NMDAR being the most complex of the glutamate-receptor subtypes. These layers of complexity are likely the result of the pivotal role of the NMDAR-glutamate system in many fundamental CNS functions and are necessary for protection against the devastating effects of uncontrolled NMDAR-mediated neurotransmission. Despite several setbacks in the development of clinically useful drugs targeting the NMDAR, a number of drugs are in clinical use and our increasing knowledge of the molecular subtleties of this pervasive receptor are a sign of excitatory times ahead for the development of future drugs for use in neurological disorders(kalia et al.,2008).