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

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

Description

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.

Sujets

• Parkinson's disease
• 2
• 3
• Méthamphétamine
• Microglía
• Dynorphin

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 31
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Wanget al. Journal of Neuroinflammation2012,9:124 http://www.jneuroinflammation.com/content/9/1/124

JOURNAL OF NEUROINFLAMMATION

R E S E A R C HOpen Access Endogenous dynorphin protects against neurotoxinelicited nigrostriatal dopaminergic neuron damage and motor deficits in mice 1†2†2 12 3 Qingshan Wang, EunJoo Shin, XuanKhanh Thi Nguyen , Quan Li , JaeHyung Bach , Guoying Bing , 4 2*1 WonKi Kim , HyoungChun Kimand JauShyong Hong

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 neurodegenerationin vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective rolesin 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 l +/+−/− more pronounced in Dynthan in Dyn. Dynshowed 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 Dynthan 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:Thein vivoresults presented here extend our previousin vitrofindings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its antiinflammatory effects. Keywords:Parkinson’s disease, 1methyl4phenyl1,2,3,6tetrahydropyridine, methamphetamine, neuroinflammation, microglia, dynorphin, prodynorphindeficient mice, nigrostriatal dopaminergic toxicity, behavioral deficit.

Background Dynorphin is an endogenous opioid peptide system that is widely distributed in various tissues. In the central ner vous system (CNS), the neurons projecting from the stri atum 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

* Correspondence: [e-mail] † Equal contributors 2 Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National University, Chunchon 200701, South Korea Full list of author information is available at the end of the article

the past decade [1]. Dynorphin and substance P have been shown to regulate nigrostriatal dopamine (DA) release, motor behavior, and learning in a reciprocal manner [25]. Conversely, the nigrostriatal DAergic systems also serve to upregulate dynorphin gene expression by interacting with D1 receptor and subsequently phosphorylating the cAMP response elements (CRE) within the prodynorphin gene promoter [6,7]. These earlier reports indicate an intimate reciprocal relationship between dynorphin and substance P in regulating DAergic neurons in the basal ganglia and further suggest possible roles of these two peptides in movement disorders, such as Parkinson’s disease (PD).

© 2012 Wang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.