Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice.
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.
Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National University, Chunchon 200-701, South Korea.
Qingshan
Q
Wang
Eun-Joo
EJ
Shin
Xuan-Khanh Thi
XK
Nguyen
Quan
Q
Li
Jae-Hyung
JH
Bach
Guoying
G
Bing
Won-Ki
WK
Kim
Hyoung-Chun
HC
Kim
Jau-Shyong
JS
Hong
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004399:Dynorphins / Q000172:deficiency / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D019957:Motor Skills Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D009498:Neurotoxins; D008694:Methamphetamine; D004399:Dynorphins