In vivo protection of striatal dopaminergic system against 1-methyl-4-phenylpyridinium neurotoxicity by phenobarbital.

We have studied the effect of a semichronic and acute treatment of phenobarbital on in vivo 1-methyl-4-phenylpyridinium ion- (MPP+)-induced neurotoxicity. A group of rats were intraperitoneally injected for 12 days with phenobarbital (80 mg/Kg of body weight, semichronic treatment) in order to induce cytochrome P450 levels in brain. At day 10 of treatment, rats received unilateral left striatal injections of 1 or 2 microg of MPP+. Two days after the injection of the toxin a dose-dependent loss of dopamine uptake along with a concomitant decrease of dopamine levels and its metabolites was produced in control rats. In phenobarbital treated animals striatal injection of 1 microg of MPP+ did not produce any effect on dopaminergic parameters but injection of 2 microg of MPP+ caused losses of dopamine levels and dopamine transporter although smaller than in control rats. TH immunohistochemistry in semichronic phenobarbital treated rats also demonstrated the protective effect of this drug against MPP+ toxicity. Dopamine uptake in synaptosomes from semichronic phenobarbital treated rats did not change with respect to the controls, thereby diminished MPP+ toxicity in phenobarbital treated rats is not due to an alterated uptake of the toxin. Neuroprotection found by intraperitoneal injection of phenobarbital 30 min before MPP+ intrastriatal injection (acute treatment) could discard the induction of cytochrome P450 as responsible for this suppressed neurotoxicity of MPP+. The neuroprotective effect of phenobarbital could be produced by its action as an excitatory amino acid antagonist or as a GABA agonist.