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Article

Original

Exp Neurobiol 2004; 13(2): 64-74

Published online December 31, 2004

© The Korean Society for Brain and Neural Sciences

Inhibition of NO Synthesis Attenuates BH4-induced Toxicity in Nigrostriatal Dopaminergic System

Yeon Joo Jang1, Yong Jin Lee2 and Onyou Hwang1*

1Department of Biochemistry and Molecular Biology and 2Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 138-736, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-3010-4279, FAX: 82-2-3010-4248
e-mail: oyhwang@amc.seoul.kr
This work was supported by a grant from the Korea Health 21 R & D Project (01-PJ8-PG1-01CN02-0003) from the Ministry of Health & Welfare, Republic of Korea.

Abstract

Parkinson's disease (PD) is a movement disorder resulting from degeneration of the dopaminergic (DArgic) nigrostriatal pathway. Although the mechanism rendering this system more vulnerable is not completely understood, oxidative stress is believed to contribute to the pathogenesis. Lines of evidence indicate that nitric oxide (NO), via nitrosylation, may participate in the death of DArgic neurons in PD. We have previously observed that tetrahydrobiopterin (BH4), an obligatory cofactor for NO synthesis, causes DArgic cell death both in vivo and in vitro. In the present study we determined whether the production of NO after intrastriatal BH4 injection might contribute to degeneration of the nigrostriatal DArgic system. We observed that intrastriatal BH4 injection caused degeneration of DArgic fibers, which was accompanied by infiltration of microglial cells to the lesion site and increased NO synthesis activity. Co-injection of the NO synthesis inhibitor L-NAME attenuated the NO synthesis and nigrostriatal degeneration of DArgic system and partly reversed the motor deficit caused by injection with BH4 alone. Taken together, the present results suggest that increased NO production, probably by activated microglia, plays an important, albeit secondary, role in degeneration of nigrostriatal DArgic system following BH4 exposure.

Keywords: tetrahydrobiopterin, nitric oxide, Parkinson's disease