Malaoxon-induced neurotoxicity in old rats: alterations in cerebral inositol lipid signalling, brain tissue calcium levels and early neuronal injury.

Effects of malaoxon (MO) on brain regional inositol, inositol monophosphate and calcium levels, as well as on early neuronal injury, were studied in old (18 months) male rats. In old rats, a dose of 8.7 mg/kg of MO caused convulsions similar to those reported earlier in parallel experiments with young male (10 weeks) rats using a dose of 39.2 mg/kg. In the convulsing old male rats, MO caused a transient decrease of cerebral inositol 1 h post MO in the piriform cortex and thalamus, whereas more persistent decreases of inositol occurred in the frontal cortex and the cerebellum. In the non-convulsing rats, a decrease of inositol was only seen in the cerebellum. Cerebral inositol-1-phosphate (Ins1P) increased in all brain regions of convulsing rats, whereas Ins1P did not change in the non-convulsing rats. Brain Ca2+ increased post MO in convulsing and non-convulsing rats in the frontal cortex, caudate and thalamus; in the piriform cortex and hippocampus increases of Ca2+ were only seen in the convulsing rats. Inositol-4-phosphate (Ins4P) remained stable in all MO-exposed rats. MO-induced early neuronal injury occurred only in the convulsing rats and was most severe in the cortex, hippocampus and the subcortical structures. Qualitatively the effects of MO in the old and young rats were, however, similar and, therefore, probably due to cholinergic brain stimulation and subsequent increase in inositol lipid signalling. These results suggest that old rats are likely to be more sensitive than the young rats to the neurotoxic effects of MO.