D-Deprenyl Protects Nigrostriatal Neurons Against 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-Induced Dopaminergic Neurotoxicity

Selegiline (L-deprenyl) is believed to render protection against l-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity to a significant extent via a free radical scavenging mechanism, which is independent of its ability to inhibit monoamine oxidase-B (MAO-B) in the brain. We investigated the hydroxyl radical (.OH) scavenging action and neuroprotective effect of D-deprenyl, its less active isomer, in MPTP-induced dopaminergic neurotoxicity in mice to test whether the chemical structure of the molecule or its biological effects contribute to this property. To achieve this goal we studied the effects of D-deprenyl on: (1) .OH production in a Fenton reaction; (2) MPTP-induced .OH generation and dopamine (DA) depletion in vivo, employing a sensitive HPLC-electrochemical procedure; and (3) formation of MPP� in vivo in the striatum following systemic administration of MPTP, employing an HPLC-photodiode array detection system. D-deprenyl inhibited ferrous citrate-induced .OH in vitro (0.45 �M) and MPTP-induced .OH in vivo in substantia nigra (SN) and in the striatum (1.0 mg/kg, i.p.). D-deprenyl did not, but L-deprenyl (0.5 mg/kg dose) did significantly inhibit formation of MPP� in the striatum 90 min following systemic MPTP injection. It failed to affect MAO-B activity at 0.5 mg/kg in the striatum, but effectively blocked MPTPinduced striatal DA depletion. The potency of D-deprenyl to scavenge MPTP-induced .OH in vivo and to render protection against the dopaminergic neurotoxicity without affecting dopamine turnover, MAO-B activity, or formation of MPP� in the brain indicates a direct involvement of .OH in the neurotoxic action of MPTP and antioxidant effect in the neuroprotective action of deprenyl