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

Qingshan Wang, Eun Joo Shin, Xuan Khanh T. Nguyen, Quan Li, Jae Hyung Bach, Guoying Bing, Won Ki Kim, Hyoung Chun Kim, Jau Shyong Hong

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63 Scopus citations

Abstract

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.

Original languageEnglish
Article number583
JournalJournal of Neuroinflammation
Volume9
DOIs
StatePublished - Jun 13 2012

Bibliographical note

Funding Information:
This study was supported by a grant (#2012K001115) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea and in part by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences, USA. This work was also, in part, supported by a grant from the Bio & Medical Technology Development Program through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea. Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 program.

Keywords

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Behavioral deficit
  • Dynorphin
  • Methamphetamine
  • Microglia
  • Neuroinflammation
  • Nigrostriatal dopaminergic toxicity
  • Parkinson's disease
  • Prodynorphin-deficient mice

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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