Restoration and putative protection in Parkinsonism

Synergistic antiparkinsonian actions of different classes of putative therapeutic agents co-administered with a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-Dopa) (5 mg/kg) in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as well as the restorative actions of those compounds in suprathreshold L-Dopa-tolerant MPTP-treated mice subjected to "wearing-off" of L-Dopa efficacy were assessed in a series of experiments. The classes of compounds studied included the noncompetitive NMDA antagonists, memantine, amantadine and MK-801, the anticonvulsive and putative anticonvulsive agents, lamotrigine, FCE 26743, phenytoin, the monoamine oxidase inhibitors, L-Deprenyl, amiflamine, alpha-ethyltryptamine, clorgyline and guanfacine. In this final case, the restorative effects of clonidine and guanfacine were antagonized by the alpha(2)-adrenoceptor antagonist, yohimbine, but not the alpha(1)-adrenoceptor antagonist, prazosin. Within each class of potentially therapeutic agents a differential restorative efficacy was obtained, but the combination of different doses of apomorphine with clonidine failed to restore motor activity. Finally, the neuroprotective actions of acute and subchronic administration of the nitrone spin-trapping compound, alpha-phenyl-tert-butyl nitrone upon the spontaneous motor behaviour and striatal dopamine concentrations of MPTP-treated mice was examined.