title: Region-specific causal mechanism in the effects of ammonia on cerebral glucose metabolism in the rat brain.
abstract: Ammonia, which is considered to be the main agent responsible for hepatic encephalopathy, inhibits oxidative glucose metabolism in the brain. However, the effects of ammonia on cerebral glucose metabolism in different brain regions remains unclear. To clarify this issue, we added ammonia directly to fresh rat brain slices and measured its effects on glucose metabolism. Dynamic positron autoradiography with [(18)F]2-fluoro-2-deoxy-D-glucose and 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) colorimetric assay revealed that ammonia significantly increased the cerebral glucose metabolic rate and depressed mitochondrial function, as compared to the unloaded control in each of the brain regions examined (cerebral cortex, striatum, and cerebellum), reflecting increased glycolysis that compensates for the decrease in aerobic metabolism. Pre-treatment with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, significantly attenuated these changes induced by ammonia in cerebellum, but not in cerebral cortex or striatum. The addition of ammonia induced an increase in cyclic guanosine monophosphate (cGMP) levels in cerebellum, but not in cerebral cortex or striatum, reflecting the activation of the NMDA receptor-nitric oxide-cGMP pathway. These results suggested that NMDA receptor activation is responsible for the impairment of glucose metabolism induced by ammonia specifically in cerebellum.
authors.affiliation: Department of Neuropsychiatry, University of Fukui, Fukui, Japan. maruoka@u-fukui.ac.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Maruoka
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Murata
authors.forename: Naoto
authors.initials: N
authors.lastname: Omata
authors.forename: Hironori
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Okazawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wada
mesh_terms: D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001345:Autoradiography; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D000641:Ammonia; D005947:Glucose