Ammonia-mediated LTP inhibition: effects of NMDA receptor antagonists and L-carnitine.
Because hyperammonemia is thought to contribute to the pathogenesis of hepatic encephalopathy, we examined the effects of ammonia on ATP levels, neuronal morphology, and synaptic function in rat hippocampal slices. Although ammonia did not alter ATP levels supported by 10 mM glucose, ammonia significantly depressed ATP levels in the presence of 3.3 mM glucose or 10 mM pyruvate, suggesting effects on respiratory energy metabolism. Ammonia also impaired synaptic function and neuronal integrity sustained by pyruvate. In 10 mM glucose, ammonia inhibited the induction and maintenance of long-term potentiation (LTP) in a concentration-dependent fashion. These inhibitory effects of ammonia were overcome by L-carnitine. DL-APV, an antagonist of NMDA receptors, also diminished the effects of ammonia on ATP levels and LTP induction, indicating that ammonia impairs neuronal function via altered metabolism and untimely NMDA receptor activation. These results suggest that L-carnitine and NMDA receptor antagonists have the potential to preserve neuronal function during hyperammonemia.
Izumi
Yukitoshi
Y
Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, USA. Izumiy@psychiatry.wustl.edu
Izumi
Masayo
M
Matsukawa
Mio
M
Funatsu
Michiyo
M
Zorumski
Charles F
CF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000641:Ammonia / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002331:Carnitine / Q000494:pharmacology* / Q000627:therapeutic use; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D022124:Hyperammonemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D000641:Ammonia; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D002331:Carnitine