Ketamine, at low dose, decrease behavioural alterations in epileptic diseases induced by pilocarpine in mice.

Objective: The objective of the present study was to evaluate the effect of low-dose of ketamine, in short-term, on behavioral impairment and acute neuronal death in the cerebral cortex during the acute phase in a model of epileptic mouse induced by pilocarpine.Methods:Ketamine was administrated (10 mg/kg) intraperitoneally, 30 min before pilocarpine injection (100 mg/kg) in the first group. The second group received the same dose of ketamine 30 min after pilocarpine injection. The effect of ketamine on behavioral disorders and cerebral neuronal integrity in epileptic mice was evaluated.Results:Clinical observations and behavioural tests relate a reduction in behavioural dysfunctions in mice treated with ketamine. Interestingly, treatment of mice with low dose of ketamine decreased the clinical symptoms (movements of the vibrios, nods of the head, and movements of the whiskers), especially when administered before epilepsy induction. Furthermore, the administration of ketamine limits oedema in the hippocampus, neuronal degeneration and gliosis in the different cortical layers. These results could be explained by NMDA receptors inhibition by ketamine.Conclusion:Therefore, it appears that ketamine is endowed with a potential neuroprotective effect and can reduce the severity of neurodegeneration, especially when administrated before Status Epilepticus (SE) installation.

Activation of the phagocyte NADPH oxidase/NOX2 and myeloperoxidase in the mouse brain during pilocarpine-induced temporal lobe epilepsy and inhibition by ketamine.

Excessive reactive oxygen species (ROS) production can induce tissue injury involved in a variety of neurodegenerative disorders such as neurodegeneration observed in pilocarpine-induced temporal lobe epilepsy. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist has beneficial effects in pilocarpine-induced temporal lobe epilepsy, when administered within minutes of seizure to avoid the harmful neurological lesions induced by pilocarpine. However, the enzymes involved in ROS productions and the effect of ketamine on this process remain less documented. Here we show that during pilocarpine-induced epilepsy in mice, the expression of the phagocyte NADPH oxidase NOX2 subunits (NOX2/gp91phox, p22phox, and p47phox) and the expression of myeloperoxidase (MPO) were dramatically increased in mice brain treated with pilocarpine. Interestingly, treatment of mice with ketamine before or after pilocarpine administration decreased this process, mainly when injected before pilocarpine. Finally, our results showed that pilocarpine induced p47phox phosphorylation and H2O2 production in mice brain and ketamine was able to inhibit these processes. Our results show that pilocarpine induced NOX2 activation to produce ROS in mice brain and that administration of ketamine before or after the induction of temporal lobe epilepsy by pilocarpine inhibited this activation in mice brain. These results suggest a key role of the phagocyte NADPH oxidase NOX2 and MPO in epilepsy and identify a novel effect of ketamine.