Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice

Journal of Neuroinflammation

Jau-Shyong Hong²  Hyoung-Chun Kim⁴  Won-Ki Kim¹  Guoying Bing³  Jae-Hyung Bach⁴  Quan Li²  Xuan-Khanh Thi Nguyen⁴  Eun-Joo Shin⁴  Qingshan Wang² 

[1] Department of Neuroscience, College of Medicine, Korea University, Seoul, 136-705, South Korea;Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA;Department of Anatomy and Neurobiology, College of Medicine, University of Kentucky, Lexington, KY, 40536, USA;Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National University, Chunchon, 200-701, South Korea

关键词: behavioral deficit.;    nigrostriatal dopaminergic toxicity;    prodynorphin-deficient mice;    dynorphin;    microglia;    neuroinflammation;    methamphetamine;    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;    Parkinson’s disease;   

Others  :  1212533
DOI  :  10.1186/1742-2094-9-124

 received in 2011-12-06, accepted in 2012-06-13,  发布年份 2012

【 摘 要 】

Background

The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo.

Methods

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson’s disease, were administered to wild-type (Dyn^+/+) and prodynorphin-deficient mice (Dyn^−/−). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR).

Results

Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn^-l- than in Dyn^+/+. Dyn^−/− showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn^+/+. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn^−/− than in Dyn^+/+. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn^−/− than in Dyn^+/+. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP.

Conclusions

The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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