Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity

Haruki Odaka; Tadahiro Numakawa; Naoki Adachi; Yoshiko Ooshima; Shingo Nakajima; Yusuke Katanuma; Takafumi Inoue; Hiroshi Kunugi

doi:10.1371/journal.pone.0099271

Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity

PLoS One. 2014 Jun 10;9(6):e99271. doi: 10.1371/journal.pone.0099271. eCollection 2014.

Authors

Haruki Odaka¹, Tadahiro Numakawa², Naoki Adachi², Yoshiko Ooshima³, Shingo Nakajima², Yusuke Katanuma¹, Takafumi Inoue⁴, Hiroshi Kunugi²

Affiliations

¹ Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
² Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Core Research for Evolution Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
³ Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.

Abstract

Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H₂O₂ exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H₂O₂ was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H₂O₂, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca²⁺ channel demonstrated a survival effect against H₂O₂. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H₂O₂.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport System X-AG / metabolism
Animals
Cabergoline
Cell Death / drug effects
Cells, Cultured
Cerebral Cortex / pathology
Ergolines / pharmacology*
Extracellular Signal-Regulated MAP Kinases / metabolism
Glutamic Acid / toxicity
Hydrogen Peroxide / toxicity
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Signaling System / drug effects
Models, Biological
Neurons / drug effects
Neurons / enzymology
Neurons / pathology*
Neuroprotective Agents / pharmacology
Neurotoxins / toxicity*
Oxidative Stress / drug effects*
Rats, Wistar
Receptors, Dopamine D2 / agonists*
Receptors, Dopamine D2 / metabolism
Time Factors
Up-Regulation / drug effects
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Amino Acid Transport System X-AG
Ergolines
Neuroprotective Agents
Neurotoxins
Receptors, Dopamine D2
Glutamic Acid
Hydrogen Peroxide
Extracellular Signal-Regulated MAP Kinases
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Cabergoline

Grants and funding

This study was supported by the Intramural Research Grant (No. 24-11) for Neurological and Psychiatric Disorders of NCNP (http://www.ncnp.go.jp/) and CREST program “creation of a novel technology towards diagnosis and treatment based on understanding of molecular pathogenesis of psychiatric and neurological disorders” (No. 08062571) of JST (http://www.sss.jst.go.jp/info/index.html) (T.N., N.A. and H.K.). This project was also supported by Takeda Science Foundation (http://www.takeda-sci.or.jp/) (T.N.), a grant from Grant-in-Aid for Scientific Research (B) (JSPS KAKENHI Grant Number 24300139) (http://www.jsps.go.jp/english/index.html) (T.N.), and Grant-in-Aid for Challenging Exploratory Research (JSPS KAKENHI Grant Number 25640019) (http://www.jsps.go.jp/english/index.html) (T.N.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.