Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity

Abstract

Intranigral infusion of 1-Methyl-4-phenylpyridinium ion (MPP+, 2.1-16.8 nmol) dose-dependently injured nigral neurons as reflected by reduced dopamine levels in the ipsilateral striatum four days after the infusion of this toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Coadministration of deprenyl (4.2 nmol) with MPP+ into the substantia nigra protected against MPP(+)-induced moderate (20-50%) but not severe (over 70%) nigral injury as reflected in striatal dopamine reductions. However, supplementary treatment with deprenyl (0.25 mg/kg, s.c., twice daily for 4 days) after intranigral infusion of MPP+ significantly rescued nigral neurons from more severe damage caused by a higher MPP+ does (8.4 nmol) manifested by a lesser striatal dopamine decrease (-31%) compared to the non-deprenyl treated group (-70%). Thus, in addition to the blockade of bioactivation of MPTP, deprenyl can protect and/or rescue nigral neurons from MPP(+)-induced dopaminergic neurotoxicity. These in vivo data add further evidence to suggest that deprenyl, a putative and clinically unproven neuroprotective agent, may be of value in slowing the progressive nigral degeneration in "early" Parkinson's disease, but may prove to be less so in its terminal stages.

Role of the Redox Protein Thioredoxin in Cytoprotective Mechanism Evoked by (-)-Deprenyl

“…Furthermore, increases in endogenous Trx levels seem to correlate with the extent of cellular protection from MPP ϩ -induced apoptosis in primary neuronal cultures of mouse midbrain dopaminergic neurons. These findings are in accord with prior reports that selegiline protects nigrostriatal dopaminergic neurons from oxidative injury caused by MPP ϩ in both in vitro preparations (Mytilineou and Cohen, 1985;Vizuete et al, 1993) and in vivo (Wu et al, 1995). Mytilineou and Cohen (1985) proposed a direct neuroprotective action of selegiline against MPP ϩ -induced neurotoxicity in midbrain dopamine cell cultures.…”

“…A recent in vivo study indicated that induction of Trx and related pro-survival proteins (superoxide dismutase, catalase, and GSH peroxidase) protect midbrain nigral neurons from MPTP-induced neurotoxicity (Kojima et al, 1999). Our previous in vivo data also indicate that selegiline protects A9 dopaminergic nigral neurons from oxidative injury caused by MPP ϩ , the toxic metabolite of MPTP (Wu et al, 1995). It has been shown to increase levels of reactive oxygen species, such as reactive hydroxyl radicals, which can react with polyunsaturated fatty acids to generate peroxyl lipid radicals, and the related toxic species, malondialdehyde and 4-hydroxy-2,3-nonenal (Chiueh et al, 1994;Rauhala et al, 1998).…”

“…However, this proposal was supplanted by a more prominent hypothesis that selegiline protects against MPTP-induced nigral degeneration simply through its known inhibitory action on MAO-B, which participates in converting MPTP to its toxic metabolite MPP ϩ (Cohen et al, 1984;Chiueh, 1988;Heikkila et al, 1991). A decade later, this direct neuroprotection hypothesis of selegiline was substantiated by in vivo studies showing that selegiline indeed prevents MPP ϩ -induced neurotoxicity (Vizuete et al, 1993;Wu et al, 1995). However, some of the in vivo results suggest that selegiline protects and rescues A9 nigral neurons against oxidative stress and degeneration caused by MPP ϩ via mechanisms independent of its capacity to inhibit MAO-B enzymatic activity.…”

“…For instance, selegiline scavenges reactive oxygen species and suppresses the generation of cytotoxic hydroxyl radicals and the peroxidation of brain lipids produced by MPP ϩ in the rat brain in vivo (Wu et al, 1995). It also prevents the ironcatalyzed auto-oxidation of dopamine to melanin.…”

“…During the past 2 decades, basic studies revealed that selegiline prevents the parkinsonism phenomena caused by MPTP and nigral injury evoked by MPP ϩ in cells and animal models (Burns et al, 1983;Cohen et al, 1984;Mytilineou and Cohen, 1985;Wu et al, 1995). Similar neuroprotective effects of selegiline have been observed in animals and cells treated with other neurotoxins, such as methyl-␤-acetoxyethyl-2-chloroethylamine, 6-hydroxydopamine, N-(2-chloroethyl)-Nethyl-2-bromobenzylamine, 5,6-dihydroxyserotonin, and 3,4-methylenedioxymethamphetamine, by a mechanism that cannot be explained solely by its inhibitory effect on MAO-B Sprague and Nichols, 1995).…”