Cannabinoids and Neuroprotection in Global and Focal Cerebral Ischemia and in Neuronal Cultures

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Abstract
Marijuana and related drugs (cannabinoids) have been proposed as treatments for a widening spectrum of medical disorders.R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate(R(+)-WIN 55212-2), a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats. The less active enantiomerS(−)-WIN 55212-3 was ineffective, and the protective effect ofR(+)-WIN 55212-2 was blocked by the specific central cannabinoid (CB1) cannabinoid receptor antagonistN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride.R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons fromin vitrohypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observedin vivo, thisin vitroeffect was not stereoselective and was insensitive to CB1and CB2receptor antagonists. Cannabinoids may have therapeutic potential in disorders resulting from cerebral ischemia, including stroke, and may protect neurons from injury through a variety of mechanisms.