title: Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction.
abstract: The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of γ-glutamate-cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD.
authors.affiliation: The School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Chi-Rei
authors.initials: CR
authors.lastname: Wu
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
authors.affiliation: Department of Medicinal Botanicals and Health Care, Dayeh University, Changhua, Taiwan.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Huang
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan. Electronic address: cwtsai@mail.cmu.edu.tw.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005721:Glutamate-Cysteine Ligase / Q000032:analysis / Q000378:metabolism; D005980:Glutathione Reductase / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000502:physiology; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000032:analysis / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000378:metabolism
chemical_list: D045784:Abietanes; D000975:Antioxidants; D010936:Plant Extracts; D017392:Thiobarbituric Acid Reactive Substances; D051028:bcl-2-Associated X Protein; D016627:Oxidopamine; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D011065:Poly(ADP-ribose) Polymerases; D005721:Glutamate-Cysteine Ligase; C018381:salvin
keywords: Antioxidative enzymes; Apoptosis; Carnosic acid; Neuroprotection; Wistar rats