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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 number124
JournalJournal of Neuroinflammation
Volume9
DOIs
Publication statusPublished - 2012 Jun 13

Fingerprint

Dynorphins
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopaminergic Neurons
Neurotoxins
Methamphetamine
Substantia Nigra
Opioid Peptides
Neuroprotective Agents
Reverse Transcription
Parkinson Disease
Rodentia
Dopamine
Anti-Inflammatory Agents
Immunohistochemistry
High Pressure Liquid Chromatography
Inflammation
Phenotype
Polymerase Chain Reaction
Brain
Therapeutics

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

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

Cite this

Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice. / Wang, Qingshan; Shin, Eun Joo; Nguyen, Xuan Khanh T; Li, Quan; Bach, Jae Hyung; Bing, Guoying; Kim, Won-Ki; Kim, Hyoung Chun; Hong, Jau Shyong.

In: Journal of Neuroinflammation, Vol. 9, 124, 13.06.2012.

Research output: Contribution to journalArticle

Wang, Qingshan ; Shin, Eun Joo ; Nguyen, Xuan Khanh T ; Li, Quan ; Bach, Jae Hyung ; Bing, Guoying ; Kim, Won-Ki ; Kim, Hyoung Chun ; Hong, Jau Shyong. / Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice. In: Journal of Neuroinflammation. 2012 ; Vol. 9.
@article{5b2e5e83c5b0417b885d30d5252ddba5,
title = "Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice",
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.",
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",
author = "Qingshan Wang and Shin, {Eun Joo} and Nguyen, {Xuan Khanh T} and Quan Li and Bach, {Jae Hyung} and Guoying Bing and Won-Ki Kim and Kim, {Hyoung Chun} and Hong, {Jau Shyong}",
year = "2012",
month = "6",
day = "13",
doi = "10.1186/1742-2094-9-124",
language = "English",
volume = "9",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice

AU - Wang, Qingshan

AU - Shin, Eun Joo

AU - Nguyen, Xuan Khanh T

AU - Li, Quan

AU - Bach, Jae Hyung

AU - Bing, Guoying

AU - Kim, Won-Ki

AU - Kim, Hyoung Chun

AU - Hong, Jau Shyong

PY - 2012/6/13

Y1 - 2012/6/13

N2 - 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.

AB - 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.

KW - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

KW - Behavioral deficit

KW - Dynorphin

KW - Methamphetamine

KW - Microglia

KW - Neuroinflammation

KW - Nigrostriatal dopaminergic toxicity

KW - Parkinson's disease

KW - Prodynorphin-deficient mice

UR - http://www.scopus.com/inward/record.url?scp=84862234112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862234112&partnerID=8YFLogxK

U2 - 10.1186/1742-2094-9-124

DO - 10.1186/1742-2094-9-124

M3 - Article

C2 - 22695044

AN - SCOPUS:84862234112

VL - 9

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

M1 - 124

ER -