The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease. Ebselen also prevents peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP(+), in vivo in rat brain. Moreover, Ebselen inhibits MPP(+)-induced toxicity in PC12 cells, without interacting with the dopamine uptake system. Our results demonstrate that compounds which prevent mitochondrial dysfunction and free radical production may be useful as preventive treatment of Parkinson's disease.
Moussaoui
S
S
Aventis Pharma, CNS Program, Centre de Recherche de Vitry-Alfortville (Building CRV8), 13, quai Jules Guesde, Vitry sur Seine Cedex, 94403, France.
Obinu
M C
MC
Daniel
N
N
Reibaud
M
M
Blanchard
V
V
Imperato
A
A
D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001798:Blood Proteins / Q000494:pharmacology; D002144:Callithrix; D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006540:Herbicides / Q000493:pharmacokinetics / Q000633:toxicity; D054833:Isoindoles; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D018716:Molecular Mimicry; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014316:Tritium
D000975:Antioxidants; D001393:Azoles; D001798:Blood Proteins; D005609:Free Radicals; D006540:Herbicides; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; D014316:Tritium; C042986:ebselen; D005979:Glutathione Peroxidase; D015655:1-Methyl-4-phenylpyridinium