Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity.
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.
Wu
R M
RM
Unit on Neurotoxicology and Neuroprotection, National Institute of Mental Health, NIH Clinical Center 10/3D-41, Bethesda, Maryland, USA.
Murphy
D L
DL
Chiueh
C C
CC
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis; D015259:Dopamine Agents / Q000633:toxicity*; D004347:Drug Interactions; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects*
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D012642:Selegiline; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine