MEMANTINE, A NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST IMPROVES HYPERAMMONEMIA-INDUCED ENCEPHALOPATHY AND ACUTE HEPATIC-ENCEPHALOPATHY IN RATS

The aim of this study was to investigate the possible role of N-methyl -D-aspartate (NMDA)-receptor overactivity in two different experimenta l rat models of encephalopathy: subacute encephalopathy caused by seve re hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute h epatic encephalopathy caused by complete liver ischemia (LIS rats). Th e effect of the noncompetitive NMDA-receptor antagonist memantine (int raperitoneal [i.p.] 10-20 mg/kg bw or intravenous [i.v.] 5 mg/kg bw) w as studied on the severity of encephalopathy by assessment of clinical grading and electroencephalogram (EEG) spectral analysis, on plasma a mmonia concentrations, amino acid concentrations in cerebrospinal flui d (CSF), intracranial pressure (ICP), and brain water content. Both ra t models developed encephalopathy within 3 to 6 hours, associated with increased CSF glutamate and aspartate concentrations and increased IC P and brain water content. Memantine administration in AI-PCS and LIS rats resulted in a significant improvement in clinical grading and les s slowing of EEG activity (P < .05), and smaller increases in CSF glut amate (P < .05) concentrations. Moreover, ICP and brain water content were significantly lower in memantine-treated AI-PCS rats than in untr eated AI-PCS rats (P < .05). Memantine had no significant effect on IC P and brain water content in LIS rats, and on ammonia concentrations i n both models. These results indicate that NMDA-receptor activation mi ght be involved in the pathogenesis of hyperammonemia-induced encephal opathy and of acute hepatic encephalopathy caused by LIS.