NMDA antagonists stroke

Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J. Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 2000 31 347-354. 

Danysz W, Parsons CG, Mobius HJ, et al (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer s disease—an unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2 85-97 Davis SM, Lees KR, Albers GW, et al (2000) Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 31 347-354 DeKeyser J (1991) Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 14 562-565 Del Dotto P, Pavese N, Gambaccini G, et al (2001) Intravenous amantadine improves levodopa-induced dyskinesias an acute double-blind placebo-controlled study. Mov Disord 16 515-520... 

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). 

Table 10.2 Treatment of stroke by NMDA antagonists during phase trials... 

Helfaer M. A., Ichord R. N., Martin L. J., Hurn P. D., Castro A., and Traystman R. J. (1998). Treatment with the competitive NMDA antagonist GPI 3000 does not improve outcome after cardiac arrest in dogs. Stroke 29 824-829. 

Lees K. R. (1997). Cerestat and other NMDA antagonists in ischemic stroke. Neurology 49 S66-S69. 

Minematsu K., Fisher M., Li L., Davis M. A., Knapp A. G., Cotter R. E., McBumey R. N., and Sotak C. H. (1993). Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted MRI. Neurology 43 397 403. 

Since no proven effective therapy for neuronal injury, or degeneration, is yet known, and, for example, stroke alone is one of the leading causes of death in many countries, the importance of finding such thereapeutic NMDA antagonists is self-evident. It will be important to determine whether certain NMDA antagonists are more effective or have fewer side effects than others in specific disease states. 

Keywords Ionotropic receptors Co-agonism NMDA antagonists Glycine antagonists Stroke Pain Metabotropic receptors Epilepsy... 

Acute stroke NMDA antagonists glycine antagonists kainate antagonists mGluj/, agonists... 

Keywords NMDA Glycine antagonists Stroke Indole-2-carboxylates Benzoazepines Pyrido[2,3-()]pyrazines... 

Albers GW, Atkinson RP, Kelley RE Rosenbaum DM. (1995). Safety, tolerability and pharmacokinetics of the NMDA antagonist dextrorphem in patients with acute stroke. Stroke 26, 254-258. 

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. 

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