NMDA receptors stroke

On the pathophysiological side, hyperactive nNOS has been implicated in A/-methyl-D-aspartate (NMDA)-receptor-mediated neuronal death in cerebrovascular-stroke. Some disturbances of smooth muscle tone within the gastrointestinal tract (e.g., gastroesophageal reflux disease) may also be related to an overproduction of NO by nNOS in peripheral nitrergic nerves. 

Finally, AIDS dementia has parallels with cerebral ischemia or stroke and again the key mechanism appears to involve overactivation of glutamate receptors, in particular the NMDA receptor, followed by excessive influx of calcium and the generation of free radicals. 

Keywords Glutamate receptors Ionotropic Metabotropic AMPA NMDA Kainate Stroke Traimiatic brain injury Alzheimer s disease Parkinson s disease ... 

The toxic action of NO has an important role, especially in nerve systems. It is assumed that during a stroke, for example, excess production of NO leads to death of nerve cells. Direct modification of ligand-gated ion chaimels, such as the receptor for N-methyl-D-aspartate (NMDA receptor), by NO has a special role in coimection with this. 

Sebastiao AM, de Mendonca A, Moreira T, Ribeiro JA (2001) Activation of synaptic NMDA receptors by action potential-dependent release of transmitter during hypoxia impairs recovery of synaptic transmission on reoxygenation. J Neurosci 21(21) 8564-8571 Shen H, Chen GJ, Harvey BK, Bickford PC, Wang Y (2005) Inosine reduces ischemic brain injury in rats. Stroke 36(3) 654-659... 

Ikonomidou C. and Turski L. (2002). Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury Lancet Neurol. 1 383-386. 

PCP inhibits brain nitric oxide synthase irreversibly (Osawa and Davila, 1993 Jewett et al., 1996 Klamer et al., 2005). Depending upon its levels, nitric oxide acts as a neuroprotective or neurodestructive molecule (Lipton, 1993 Lipton et al., 1998). NMDA receptor antagonists that have treated ischemic injury of the brain in animal models with some benefit are presented in Tables 10.1 and 10.2. All studies on their use in humans have been unsuccessful because they not only block normal neuronal function, but also produce serious side effects such as headache, anxiety, agitation, nausea, vomiting, hallucinations, dizziness, and coma (Schehr, 1996 Koroshetz and Moskowitz, 1996 Ratan et al., 1994). Clinical trials of NMDA antagonists for stroke and traumatic brain injury have been abandoned (Kemp and McKeman, 2002 Lees et al., 2000 Sacco et al., 2001). 

Several NMDA receptor antagonists have been synthesized and tested in stroke models, epilepsy models, and in clinical trials. Many of the antagonists are limited by side effects such as hemodynamic abnormalities, hypotension, neuronal vacuolation, memory disturbances, cognitive disturbances, motor dysfunction, seizures, hallucinations, unpleasant dreams, psychotomimetic episodes, and other effects. This has made the search difficult for NMDA receptor antagonists that can be used as neu-roprotective agents. 

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