GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum.
We investigated both the antioxidant activities of GPI1046, a non-immunosuppressive derivative of FK506, and the in vivo neuroprotective properties against toxicity of intracerebroventricular 6-hydroxydopamine (6-OHDA) in mice. The 6-OHDA-induced reduction in dopamine and its metabolites in the striatum was significantly normalized by daily administration of GPI1046. Moreover, GPI1046 significantly reduced lipid peroxidation in vivo. Further, GPI1046 significantly increased striatal glutathione (GSH) levels by activating GSH synthesis, although the striatal catalase and superoxide dismutase activities did not change. We conclude that GPI1046 may have neuroprotective effects both in cell cultures and in vivo.
Tanaka
Ken-ichi
K
Department of Brain Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatacho, Okayama 700-8558, Japan. kntanaka@cc.okayama-u.ac.jp
Yoshioka
Michiyo
M
Miyazaki
Ikuko
I
Fujita
Naoko
N
Ogawa
Norio
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D020104:Immunophilins / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
D000975:Antioxidants; D015259:Dopamine Agents; C104949:GPI 1046; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D016627:Oxidopamine; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D020104:Immunophilins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D004298:Dopamine; D016559:Tacrolimus