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

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

doi:10.1186/1742-2094-9-124

Abstract

BackgroundThe 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.Methods1-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).ResultsTreatment 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.ConclusionsThe 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.

Highlights

The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain
Using Dyn−/−, we demonstrated that endogenous prodynorphin deficiency aggravated behavioral impairment and DAergic neuronal loss induced by MPTP and MA
There were three major findings of this study: (1) MPTP- and MA-elicited impairments of locomotor activity and rota-rod performance were more pronounced in Dyn−/− than in Dyn+/+; (2) these motor deficits were well correlated with greater nigrostriatal DAergic neuronal loss in Dyn−/− than in Dyn+/+ after toxin treatment; and (3) both toxins triggered higher degrees of microglial activation and M1 phenotype differentiation in Dyn−/− as compared with Dyn+/+, suggesting that overactivated microglia and amplified proinflammatory activities underlie the mechanisms of the exacerbated neurotoxic effects

Summary

Introduction

The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. In the central nervous system (CNS), the neurons projecting from the striatum to the substantia nigra (SN) contain high levels of dynorphin, which co-exists with substance P The roles of these two peptides in motor function regulation in the striatonigral pathway have been studied extensively over. The observed decreases in dynorphin mRNA levels in these 6-OHDA rats returned to near control levels after administration of levodopa (L-DOPA) or SKF38393 (D1 DAergic receptor agonist) [9]. These findings further suggest the possible involvement of dynorphin in the pathogenesis of PD. The non-selective opioid antagonist naloxone attenuated L-DOPA-induced involuntary movements in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-treated common marmosets [11]

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