MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on September 17, 2008; DOI: 10.1124/mol.108.048611

0026-895X/08/7406-1564-1575$20.00
Mol Pharmacol 74:1564-1575, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.108.048611v1
74/6/1564    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hung, S.-Y.
Right arrow Articles by Fu, W.-M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hung, S.-Y.
Right arrow Articles by Fu, W.-M.

Overexpression of Heme Oxygenase-1 Protects Dopaminergic Neurons against 1-Methyl-4-Phenylpyridinium-Induced Neurotoxicity

Shih-Ya Hung, Houng-Chi Liou, Kai-Hsiang Kang, Ruey-Meei Wu, Chun-Chiang Wen, and Wen-Mei Fu

Pharmacological Institute, College of Medicine, National Taiwan University (S.-Y.H., H.-C.L., K.-H.K., W.-M.F.); and Departments of Neurology (R.-M.W.) and Psychiatry (C.-C.W.), National Taiwan University Hospital

Heme oxygenase-1 (HO-1) is up-regulated in response to oxidative stress and catalyzes the degradation of pro-oxidant heme to carbon monoxide (CO), iron, and bilirubin. Intense HO-1 immunostaining in the Parkinsonian brain is demonstrated, indicating that HO-1 may be involved in the pathogenesis of Parkinsonism. We here locally injected adenovirus containing human HO-1 gene (Ad-HO-1) into rat substantia nigra concomitantly with 1-methyl-4-phenylpyridinium (MPP+). Seven days after injection of MPP+ and Ad-HO-1, the brain was isolated for immunostaining and for measurement of dopamine content and inflammatory cytokines. It was found that overexpression of HO-1 significantly increased the survival rate of dopaminergic neurons; reduced the production of tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin-1β (IL-1β) in substantia nigra; antagonized the reduction of striatal dopamine content induced by MPP+; and also up-regulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) expression in substantia nigra. Apomorphine-induced rotation after MPP+ treatment was also inhibited by Ad-HO-1. On the other hand, inhibition of HO enzymatic activity by zinc protoporphyrin-IX facilitated the MPP+-induced rotatory behavior and enhanced the reduction of dopamine content. HO-1 overexpression also protected dopaminergic neurons against MPP+-induced neurotoxicity in midbrain neuron-glia cocultures. Overexpression of HO-1 increased the expression of BDNF and GDNF in astrocytes and BDNF in neurons. Our results indicate that HO-1 induction exerts neuroprotection both in vitro and in vivo. Pharmacological or genetic approaches targeting HO-1 may represent a promising and novel therapeutic strategy in treating Parkinsonism.

Received May 6, 2008; accepted September 15, 2008

Address correspondence to: Wen-Mei Fu, Pharmacological Institute, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan 100. E-mail: wenmei{at}ntu.edu.tw






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics