Chapter 16 Novel sites of action for deprenyl in MPTP-parkinsonism: metabolite-mediated protection against striatal neurotoxicity and suppression of MPTP-induced increase of dopamine turnover in C57BL mice

Publisher Summary This chapter provides evidence on recent finding that l-Depreny (DEP) has neuroprotective effects against dopaminergic toxicity of MPTP and its 2’-substituted analogs in mice, which are associated with the ability of its major metabolites, 1-methamphetamine and 1-amphetamine, to block the neuronal uptake of the toxic pyridinium metabolites of 1 -methyl-4-phenyl-172,3,6-tetrahydropyridine (MPTP) and its analogs. It demonstrates that protection by a 30-min DEP postreatment against MPTP -induced decrease of striatal dopamine level is reduced when mice received SKF 525A, an inhibitor of the metabolism of DEP 10 min, prior to DEP treatment. The chapter also demonstrates that a 30-min pre- or post-treatment with DEP provides a substantial protection against striatal dopamine depletion induced by 2´Et-MPTP, which is primarily bioactivated by monoamine oxidase (MAO)-A. A 30-min post-treatment with DEP, in addition to protection against dopamine depletion, also prevents the decrease in striatal mazindol binding induced by MPTP, 2´Me-MPTP, or 2´Et-MPTP. In the study presented in the chapter it was found that A subacute DEP treatment of mice with severe injury in the terminal fields of the nigrostriatal dopaminergic system enhanced the recovery of striatal dopamine level and suppressed the MPTP-induced elevation of dopamine turnover. Deprenyl treatment was applied in a wide range of dose to mice that had received MPTp for 5 consecutive days. The effect of subacute DEP treatment on the recovery of striatal dopamine level was most pronounced at a cumulative dose of 0.8 mg/kg, indicating that higher dosage of DEP may be less beneficial.