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)

Protective action of M- and N-cholinoceptor blockers in acute ammonium intoxication

“…Thus, suppressing the activity of central Mand N-cholinoceptors afforded protection against hyperammonemia, which confirms that the cholinergic system, like the system of glutamate receptors [7,10,12], is implicated in the mechanism by which this pathological condition develops.…”

Polyamine Protection Against Chemically Induced Hepatotoxicity

“…Ornithine decarboxylase, the enzyme responsible for putrescine synthesis, has been observed to increase in rat liver at 6 and 24 hours after CCl 4 plus fructose 1,6-bisphosphat e treatment compared to CCl 4 alone (Rao and Mehendale 1989). It is believed that an additional mechanism that maintains putrescine content is the increased spermidine N 1 -acetyltransferase activity that converts spermine into spermidine and putrescine (Seiler et al 1993;Terakura et al 1995;Sugimoto et al 1994;Xiao and Casero 1996).…”

Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase

“…Inactivation of ornithine aminotransferase (L-ornithine : 2-oxoacid aminotransferase; EC 2.6.1.13; OAT) by 5-fluoromethylornithine (5FMOrn) enhances tissue ornithine concentrations (Daune et al 1988), and effectively antagonizes acute intoxications with ammonium salts (Seiler et al 1993). 5FMOrn can be given orally with the drinking water for a long time without any obvious toxic effects (Daune-Anglard et al 1993).…”