EFFECT OF THE MAO-B INHIBITOR, MDL72974, ON SUPEROXIDE-DISMUTASE ACTIVITY AND LIPID-PEROXIDATION LEVELS IN THE MOUSE-BRAIN

MDL72974 is a member of a series of MAO-B inhibitors to be used as pot ential therapeutic agents in the treatment of Parkinson's and Alzheime r's diseases. However, we have recently observed a reduction in the de nsity of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra of mice treated with MDL72974. As oxidative stress is known to p lay a significant role in the nigrostriatal pathway, analysis of the r elationship between TH+ cell losses induced by MDL72974 and by free ra dical production was investigated in the present study. Results demons trate a significant increase in superoxide dismutase (SOD) activity a key antioxidant, in the striatum and cerebellum of MDL72974-treated mi ce, presumably in response to free radical production. An increase in Lipid peroxidation levels was also observed in the striatum of these a nimals in a manner which is consistent with oxidative stress-inducing agents. We therefore suggest that MDL72974 may be detrimental to dopam inergic neurons of the nigrostriatal pathway via free radical-mediated reactions. (C) 1998 Wiley-Liss, Inc.