Abstract
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 α (TNF-α) 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.
Footnotes
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This work was supported by research grants from the National Science of Council of Taiwan.
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ABBREVIATIONS: HO, heme oxygenase; PPIX, protoporphyrin-IX; ROS, reactive oxygen species; PD, Parkinson's disease; MPP+, 1-methyl-4-phenylpyridinium; Ad, adenovirus; TNF, tumor necrosis factor; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; BDNF, brain-derived neurotrophic factor; GDNF, glia cell line-derived neurotrophic factor; TH, tyrosine hydroxylase; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; HPLC, high-performance liquid chromatography; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; moi, multiplicity of infection; PCR, polymerase chain reaction; CNS, central nervous system; [Ru(CO)3Cl2]2, tricarbonyldichlororuthenium (II) dimer; GFAP, glial fibrillary acidic protein.
- Received May 6, 2008.
- Accepted September 15, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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