Excitotoxicity antagonists

Although there is no evidence that the neuronal degeneration of AzD results, as in cardiovascular ischaemia, from the excitotoxicity of increased intracellular Ca +, some calcium channel blockers have been tried in AzD. They have had little effect but surprisingly a pyrrolidone derivative nefiracetam, which opens L-type voltage-sensitive calcium channels (VSCCs) reduces both scopolamine- and )S-amyloid-induced impairments of learning and memory in rats (Yamada et al. 1999). This effect can be overcome by VSCC antagonists, but nefiracetam has not been tried in humans. 

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

Relton, J.K. and Rothwell, N.J. (1992). Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damr e in the rat. Brain Res. Bull. 29, 243-246. 

Even in Alzheimer s disease (AD), the possible involvement of a weak excitotoxic process cannot be ruled out. Indeed, mitochondrial abnormalities (such as cytochrome oxidase alterations) [36, 37] and increased levels of markers of oxidative stress [38] have been reported in AD. This has been the rationale for testing the NMDA antagonist memantine in Alzheimer s dementia [39]. 

Excitotoxic reactions NMDA antagonists Ampakines Modulators of glutamate transporters ... 

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... 

Studies of animals with central cholinergic lesions produced by either pharmacological inhibition of choline uptake or direct excitotoxic lesions of basal forebrain cholinergic neurons have shown highly specific attentional deficits (Muir et al. 1992 Robbins et al. 1989). These animals showed deficits that might be predicted from studies of humans with AD that is, they showed increased response latency and increased responsiveness to irrelevant sensory stimuli. Studies by Vidal (1994b) have shown that administration of a nicotinic antagonist into rat prefrontal cortex impairs performance on spatial... 

Hodges H, Sowinski P, Turner JJ, et al Comparison of the effects of the 5-HTj receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain chohnergic system. Psychopharmacology 125 146-161, 1996... 

N-methyl-D-aspartate glutamate antagonists Inhibit glutamate excitotoxicity 1 drug approved... 

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