N-methyl,N-propargyl-2-phenylethylamine (MPPE), an analog of deprenyl, increases neuronal cell survival in thiamin deficiency encephalopathy

Abstract

Wernicke encephalopathy (WE) is a neurological disorder attributable to thiamin deficiency (TD). Severe TD, in humans and animals, results in highly selective lesions with a symmetrical distribution in brain regions including the mammillary bodies, thalamus, inferior colliculi, periaqueductal and periventricular regions, and inferior olivary nuclei. Experimental TD in the rat provides a robust and reproducible model that allows investigations of mechanisms underlying both apoptotic and necrotic neuronal death. (-)-Deprenyl (DEP), a selective monoamine oxidase B (MAO-B) inhibitor, has been reported to be clinically effective in the treatment of neurodegenerative disorders and to have neuroprotective and/or neurorescue properties in a variety of ex vivo and in vitro paradigms, including experimental TD. Because the metabolites of DEP, amphetamine, and methamphetamine may have adverse behavioral effects, a DEP analog, N-methyl,N-propargyl-2-phenylethylamine (MPPE) that is not metabolized to amphetamine or methamphetamine was examined in the present studies. Results showed that TD rats treated with MPPE had significantly increased neuronal cell counts compared to vehicle-treated TD rats. MPPE, like DEP, also significantly decreased the density of reactive astrocytes and the infiltration of microglia/macrophages. Chronic treatment with DEP or MPPE resulted in significant inhibition of MAO-A and MAO-B activity compared to VEH-treated animals. Thus, MPPE, an inhibitor of MAO activity, was shown to be neuroprotective in the TD model of neuronal cell death. Drug Dev. Res. 51:244–252, 2000. © 2001 Wiley-Liss, Inc.