Enhanced endogenous ornithine concentrations protect against tonic seizures and coma in acute ammonia intoxication.

Abstract

Pretreatment of mice with 5-fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase, diminishes the accumulation of ammonia in the brain after administration of ammonium acetate, and antagonizes ammonia-induced fatal tonic extensor convulsions. In about 50% of the treated animals the loss of the righting reflex and coma is prevented. Presumably these effects are based on the enhancement of urea formation by the increased liver ornithine concentrations. However, since brain ornithine concentrations are greatly enhanced by 5FMOrn, it is not excluded that ornithine has direct effects on cellular events involved in ammonia-induced seizure generation, even though 5FMOrn had no anticonvulsant properties in a series of established animal seizure models, including N-methyl-D,L-aspartate-induced convulsions. NMDA receptor antagonists are capable of preventing death, but do not protect against the generation of coma and tonic extensor convulsions in ammonium acetate intoxicated mice. Since no evidence was found for ammonia-induced glutamate release from rat hippocampus, there is no convincing evidence for the idea that the tonic convulsions are mediated by NMDA receptors. L-Methionine-D, L-sulfoximine (MSO)-induced seizures can be partially antagonized by pretreatment with 5FMOrn. However, the effect is considerably smaller than against ammonia-induced convulsions, although at the time of seizure onset brain ammonia levels of MSO-intoxicated mice were lower than in the animals receiving ammonium acetate. This suggests that MSO-convulsions are not entirely due to the elevation of brain ammonia concentrations, even though MSO administration mimics effects of ammonia on cortical inhibitory neuronal interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: N Seiler, S Sarhan, B Knoedgen, J M Hornsperger, M Sablone
• Journal: Pharmacology & toxicology (Pharmacol Toxicol) Vol. 72 Issue 2 Pg. 116-23 (Feb 1993) ISSN: 0901-9928 [Print] Denmark
• PMID: 8097310 (Publication Type: Journal Article)

Chemical References

• 5-fluoromethylornithine
• Methionine Sulfoximine
• N-Methylaspartate
• Dizocilpine Maleate
• Ammonia
• 3-Mercaptopropionic Acid
• Ornithine
• Ornithine-Oxo-Acid Transaminase
• Glutamate-Ammonia Ligase
• Strychnine
• Putrescine
• Pentylenetetrazole

Topics

• 3-Mercaptopropionic Acid
• Ammonia (antagonists & inhibitors, blood, toxicity)
• Animals
• Brain Chemistry (drug effects)
• Coma (chemically induced, prevention & control)
• Dialysis
• Dizocilpine Maleate (pharmacology)
• Electroshock
• Epilepsy, Generalized (chemically induced, prevention & control)
• Female
• Glutamate-Ammonia Ligase (metabolism)
• Methionine Sulfoximine
• Mice
• N-Methylaspartate
• Ornithine (analogs & derivatives, pharmacology, physiology)
• Ornithine-Oxo-Acid Transaminase (antagonists & inhibitors)
• Pentylenetetrazole
• Postural Balance (drug effects)
• Putrescine (metabolism)
• Strychnine