Bapm. Vogels et al., MEMANTINE, A NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST IMPROVES HYPERAMMONEMIA-INDUCED ENCEPHALOPATHY AND ACUTE HEPATIC-ENCEPHALOPATHY IN RATS, Hepatology, 25(4), 1997, pp. 820-827
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.