Effects of the memory enhancer linopirdine (Dup 996) on cerebral glucose metabolism in naive and hypoxia-exposed rats

Abstract

Linopirdine [DuP 996; 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one] represents a novel class of compounds which enhance depolarization-activated (but not basal) release of acetylcholine, dopamine and serotonin in brain slices and improve learning and memory in rodents. The effects of linopirdine on local cerebral glucose metabolism were studied by the quantitative autoradiographic 2-deoxy- d-[1- 14C]glucose method. Linopirdine administration in naive rats (0.01, 0.1, or 1.0 mg/kg, s.c.) did not significantly alter cerebral glucose metabolism in any of the regions analyzed. Since linopirdine protects against hypoxia-induced passive avoidance deficits in rats, we also examined the effects of linopirdine on cerebral metabolism after the rats were exposed to 30 min of hypoxia. Glucose metabolism was not significantly altered after hypoxic exposure, except for a small increase in some brain regions. Linopirdine administered after hypoxia decreased glucose metabolism in the hippocampus, limbic cortex, ventral hippocampal commissure, medial septum, striatum, subthalamic nucleus, zona incerta, lateral habenula, cerebral cortex, cerebellar vermis and a few thalamic nuclei. Statistically significant effects of linopirdine on glucose metabolism were observed in 22 of 56 brain regions sampled. In hypoxia-exposed rats, linopirdine altered glucose metabolism in brain regions that are implicated in learning and memory and are affected in Alzheimer's disease. Several of the affected regions are associated with the cholinergic system and may play a role in the cognitive enhancing properties of linopirdine.