The effects of temperature and scopolamine on N-methyl-D-aspartate antagonist-induced neuronal necrosis in the rat

The effects of temperature and scopolamine on dizocilpine maleate-induced n euronal necrosis in the rat cingulate/retrosplenial cortex, entorhinal/olfa ctory cortices and the dentate gyrus were studied. Mild, protracted hypothe rmia (48 h at a brain temperature of 34 degrees C), induced by a servo-cont rolled "exposure technique" in the awake female rat, significantly reduced dizocilpine maleate (5.0 mg/kg, i.p.)-induced neuronal death in the cingula te/retrosplenial and entorhinal/olfactory cortices seven days following dru g administration. Scopolamine (0.25 mg/kg, i.p.), putatively neuroprotectiv e [Olney J. W. et al. (1991) Science 254, 1515-1518], did not reduce injury in the cingulate/retrosplenial cortex of female rats following one injecti on, but did following two and three doses. Scopolamine had no significant e ffect in the other brain regions. A temperature elevation of only 1 degrees C above baseline for 48 h in awake female rats increased dizocilpine malea te-induced damage. Finally, the sex differences in N-methyl-D-aspartate ant agonist toxicity were replicated and extended to other structures, and foun d not to be due to temperature differences. Our data shaw that dizocilpine maleate neurotoxicity is temperature sensiti ve. Scopolamine treatment needed to be prolonged in order to reduce injury, and even then was only efficacious in one of three brain regions. The resu lts underscore the importance of using neuronal necrosis in several brain r egions as the endpoint and for the use of prolonged therapeutic interventio ns. Furthermore, given the potential hypothermic action of other putative n europrotective drugs, a mechanistic re-evaluation of N-methyl-D-aspartate a ntagonist-induced injury is needed, with precise brain temperature measurem ent. (C) 1999 IBRO. Published by Elsevier Science Ltd.