title: The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals.
abstract: Free radicals are involved in the pathogenesis and/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to activate glutathione (GSH), catalase (Cat) and superoxide dismutase (SOD) activating effects and its in vivo neuroprotective properties against 6-hydroxydopamine (6-OHDA) intracerebroventricularly (i.c.v.) in mice. The striatal DA turnover induced by i.c.v. injection of 6-OHDA was completely normalized by pretreatment with cabergoline. Moreover, cabergoline scavenged free radicals in vitro and significantly reduced lipid peroxidation in vitro and in vivo. Furthermore, daily administration of cabergoline to mice significantly increased striatal GSH levels by activation of RNA expressions of GSH-related enzymes, although striatal Cat and SOD activities did not change. In addition, our present results suggest that repeated administration of cabergoline attenuates both 6-OHDA-induced nigrostriatal DAergic dysfunction and DA neuronal cell death, since cabergoline also had a neuroprotective effect in the immunohistochemical experiment. In conclusion, our findings indicate that the multiple antioxidant mechanisms of cabergoline, such as activation of the GSH system and the direct free radical scavenging activity, may explain the neuroprotective effect of this ergot DA agonist.
authors.affiliation: Department of Brain Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Ken ichi
authors.initials: Ki
authors.lastname: Tanaka
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyazaki
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujita
authors.forename: Youichirou
authors.initials: Y
authors.lastname: Higashi
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.forename: Norio
authors.initials: N
authors.lastname: Ogawa
mesh_terms: D019881:Aminoacyltransferases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000077465:Cabergoline; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004873:Ergolines / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000096:biosynthesis / Q000235:genetics; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D018491:Dopamine Agonists; D004873:Ergolines; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D005980:Glutathione Reductase; D019881:Aminoacyltransferases; C093784:glutathione gamma-glutamylcysteinyltransferase; D005982:Glutathione Transferase; D005978:Glutathione; D000077465:Cabergoline