HISTAMINE-MEDIATED NEURONAL DEATH IN A RAT MODEL OF WERNICKES ENCEPHALOPATHY

Three experiments were conducted to examine the role of histamine in n euronal degeneration in a rat model of Wernicke's encephalopathy induc ed by an acute bout of pyrithiamine-induced thiamine deficiency (PTD). In the first experiment, histamine levels in medial thalamus of freel y moving PTD rats measured by microdialysis were increased (180% of co ntrols) at a prelesion stage of thiamine deficiency (treatment day 12) and further elevated 48 hr later (380%) in the same animals when necr osis was evident. Histamine levels in dialysates of the hippocampus co llected simultaneously from the same animals were unchanged at either stage of thiamine deficiency. Glutamate levels in microdialysates from the same animals were unchanged at the prelesion stage but were signi ficantly elevated on the second collection day. In a second experiment , separate groups of PTD and pairfed control (CT) rats were infused co ntinuously with either alpha-fluoromethylhistidine (FMH; 80 mg/day, i. p.), an irreversible inhibitor of histamine synthesis, or saline. FMH pretreatment produced a significant protection against PTD-induced neu ronal loss within the midline-intralaminar and anteromedial thalamic n uclei, but had no effect on damage to ventrolateral nuclei, anterovent ral nucleus, or the mammillary bodies. In a third study, histamine (80 mu g, free base) or vehicle was directly infused into the same region of medial thalamus dialyzed in experiment 1. Histamine infusion into prelesion PTD but not CT animals resulted in severe neuronal loss and gliosis. Infusion of vehicle into the same regions of PTD and CT rats produced a mild gliosis restricted to the needle tract with no evidenc e of neuronal loss. These observations together with recent evidence o f a histamine enhancement of glutamate receptor activation suggest tha t early histamine release may contribute significantly to glutamate-N- methyl-D-aspartate (NMDA)-mediated excitotoxic neuronal death in thiam ine deficiency-induced Wernicke's encephalopathy. (C) 1991 Wiley-Liss, Inc.