NEUROCHEMICAL AND PATHOLOGICAL ALTERATIONS FOLLOWING INFUSION OF LEUPEPTIN, A PROTEASE INHIBITOR, INTO THE RAT-BRAIN

It is known that proteases participate in cellular protein turnover an d eliminate abnormal and potentially toxic proteins. Disturbed proteol ysis may be responsible for generating the pathological features of so me neurodegenerative disorders. Alzheimer disease, for instance, is th e most common neurodegenerative disorder and a condition in which prot eins of the cell membrane and cytoskeleton are abnormally processed an d accumulated in the brain. It is of interest to investigate the effec t of protease inhibitors on neurons and neurotransmitter systems in th e brain. We examined neurochemical and morphological neuronal changes in the rat brain following long-term intracerebroventricular infusion of leupeptin, a potent calcium-activated protease (calpain) inhibitor. Leupeptin (5 mg) was infused into the lateral ventricle using an osmo tic minipump for 14 days. We found a significant reduction of regional choline acetyltransferase activities in the hippocampus, and of somat ostatin concentrations in the hypothalamus and entorhinal cortex. More over, leupeptin caused a wide-spread, highly significant decrease in n europeptide-Y concentrations. Leupeptin infusion produced severe degen eration of neuronal processes in both axons and dendrites, and accumul ation of electron-dense bodies in the hippocampus. The results indicat e that long-term intracerebroventricular infusion of leupeptin in the rat produces neurochemical and morphological changes resembling those of some neurodegenerative disease and aging. Abnormal proteolysis caus ed by either reduced protease or enhanced protease inhibitor activitie s might play an important role in these conditions.