Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G

The effects of a single dose of the HIV-1 coat protein gp120 given into one lateral cerebral ventricle (i.c.v.) on the expression of cyclooxygenase ty pe 2 (COX-2) and PGE, levels have been studied using Western blotting and E LISA techniques applied to brain tissue extracts obtained from the neocorte x of individual rats, one of the regions of the central nervous system wher e the viral protein causes apoptosis. The results demonstrate that COX-2 ex pression is almost doubled 6 h after a single dose (100 ng) of gp120 and th is is paralleled by a statistically significant elevation of PGE,. Enhanced COX-2 expression is implicated in the mechanisms of apoptosis evoked by gp 120 because the latter is prevented by NS398 (10 mg/kg i.p.), a selective i nhibitor of COX-2 activity. Protection is also afforded by NMDA receptor an tagonists, such as MK801 (0.3 mg/kg i.p.) and CGP040116 (10 mg/kg i.p.), an d by the free radical scavenger, U-74389G (10 mg/kg i.p.), supporting a glu tamate-mediated, excitotoxic, mechanism of apoptotic death induced by gp120 . These data together with the observation that MK801 failed to prevent gp1 20-enhanced COX-2 expression indicate that products of the arachidonic casc ade may be responsible for elevation of synaptic glutamate leading neocorti cal cells to oxidative stress and excitotoxic apoptosis. (C) 2000 Academic Press.