K. Kuki et al., NEUROCHEMICAL AND PATHOLOGICAL ALTERATIONS FOLLOWING INFUSION OF LEUPEPTIN, A PROTEASE INHIBITOR, INTO THE RAT-BRAIN, Dementia, 7(5), 1996, pp. 233-238
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.