HYPERAMMONEMIA AND HEPATIC-ENCEPHALOPATHY STIMULATE RAT CEREBRAL SYNAPTIC MITOCHONDRIAL GLUTAMATE-DEHYDROGENASE ACTIVITY SPECIFICALLY IN THE DIRECTION OF GLUTAMATE OXIDATION

The effects of hepatic encephalopathy (HE) due to thioacetamide (TAA)-induced liver failure and hyperammonemia (HA) produced by repeated i.p. administration of ammonium acetate on the activity of glutamate dehydrogenase (GIDH) in the direction of glutamate (Glu) synthesis from - (GIDH-NADH) or its oxidation to alpha-ketoglutarate (alpha-KG) (GIDH-NAD), respectively, were examined in non-synaptic and synaptic mitochondria from rat cerebral hemispheres. In non-synaptic mitochondria, HE and HA stimulated the GIDH-NADH activity by, respectively, 33% and 49%, but neither condition affected the GIDH-NAD activity. In synaptic mitochondria, HE and HA decreased the GIDH-NADH activity by, respectively, 31% and 28%, but stimulated the GIDH-NAD activity by as much as 90% (HE) and 100% (HA). Kinetic assays revealed that HA increased the V(max) of the synaptic mitochondrial GLDH-NAD by 105%, without affecting the Km for Glu. The stimulation of GIDH-NAD favors the oxidation of synaptic Glu to alpha-KG, and may represent an adaptive response serving to counteract hyperammonemia-induced decrease of cerebral alpha-KG production in other metabolic pathways.