Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease.
Exposure of mice to the herbicide paraquat has been demonstrated to result in the selective loss of dopaminergic neurons of the substantia nigra, pars compacta (SNpc) akin to what is observed in Parkinson disease (PD). In this study, we investigate the efficacy of two synthetic superoxide dismutase/catalase mimetics (EUK-134 and EUK-189) in protecting against paraquat-induced dopaminergic cell death in both the rat dopaminergic cell line 1RB3AN27 (N27) and primary mesencephalic cultures in vitro and in adult mice in vivo. Our data demonstrate that pretreatment with either EUK-134 or EUK-189 significantly attenuates paraquat-induced neurotoxicity in vitro in a concentration-dependent manner. Furthermore, systemic administration of EUK-189 decreases paraquat-mediated SNpc dopaminergic neuronal cell death in vivo. These findings support a role for oxidative stress in paraquat-induced neurotoxicity and suggest novel therapeutic approaches for neurodegenerative disorders associated with oxidative stress such as PD.
Peng
Jun
J
Buck Institute for Age Research, Novato, California 94945 and Eukarion, Inc., Bedford, MA 01730, USA.
Stevenson
Fang Feng
FF
Doctrow
Susan R
SR
Andersen
Julie K
JK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002374:Catalase / Q000737:chemistry* / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008345:Manganese / Q000378:metabolism; D017895:Manganese Compounds / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology*; D051381:Rats; D012459:Salicylates / Q000494:pharmacology; D013378:Substantia Nigra / Q000473:pathology*; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; C433928:EUK-134; C436526:EUK-189; D017895:Manganese Compounds; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D012459:Salicylates; D008345:Manganese; D002374:Catalase; D013482:Superoxide Dismutase; D010269:Paraquat; D004298:Dopamine