RESUMO
There is a recent evidence supporting that neuronal injury may be dependent upon the generation of the free radical nitric oxide [NO] with the subsequent induction of programmed cell death [apoptosis]. The aim of the present study was to assess the contribution of NO and the possible neuroprotective effect of two drugs modulating NO-apoptotic pathway, namely minocycline and ebselen, in L-2 chloropropionic acid [L-CPA] -induced neuronal injury in the rat. The present study was conducted on 40 male albino rats that were divided into: Group I; normal rats that served as control Group II; rats in which cerebellar neuronal injury was induced by L-CPA, Groups III and IV; rats with L-CPA -induced neuronal injury that received minocycline and ebselen respectively for 2 days starting half an hour before dosing with L-CPA. Forty-eight hours following L-CPA administration, signs characteristic of cerebellar ataxia, including hind limb weakness and abnormal gait were recorded, The ability of the rat to lift [retract] its hindlimbs was measured. Rats were then exsanguinated, cerebellum isolated for the determination of cerebellar: Nitric oxide synthase [NOS] activity, caspase-3 activity as an index of apoptosis, sodium concentration as a measure of cerebellar edema and glutamate concentration as a marker for cerebellar granule cell necrosis. The results of the present study demonstrated a significant increase in: the time taken by rats to retract hindlimbs, cerebellar NOS and caspase-3 activities as well as in sodium concentration, in group II compared to group I. A significant decrease in cerebellar glutamate concentration could be observed in group II compared to group I. Treatment with minocycline and ebselen resulted in significant decrease in cerebellar NOS activity and active caspase-3 and sodium concentrations together with a significant increase in cerebellar glutamate concentration compared to non-treated rats receiving L-CPA. In conclusion, the present work demonstrated that neuronal injury, induced by L-CPA, is associated with increased NOS activity resulting in increased NO production, which has been suggested to play a role in the mediation of that injury. We demonstrated that drugs that reduce the activity of NOS and caspases, like minocycline and ebselen are capable of blocking neurotoxicity. These results provide an experimental rationale for the evaluation of the role of NO-apoptotic pathway and the possible therapeutic potential of minocycline and ebselen in human neurological disorders