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Protection of Primary Dopaminergic Midbrain Neurons by GPR139 Agonists Supports Different Mechanisms of MPP(+) and

Kirsten Bayer Andersen1, Jens Leander Johansen1, Morten Hentzer2

  • 1Department of Neurodegeneration, H. Lundbeck A/S Valby, Denmark.

Frontiers in Cellular Neuroscience
|July 23, 2016
PubMed

Insights

G-protein coupled receptor 139 (GPR139) agonists show neuroprotection for dopaminergic neurons against MPP+-induced degeneration. This suggests potential therapeutic applications for GPR139 in Parkinson's disease models.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • G-protein coupled receptor 139 (GPR139) is expressed in brain regions critical for motor control.
  • The precise function and signaling pathways of GPR139 remain poorly understood, with conflicting literature findings.
  • Dopaminergic (DA) neuronal degeneration is a hallmark of Parkinson's disease (PD).

Purpose of the Study:

  • To investigate the neuroprotective potential of GPR139 agonism in experimental models of DA neuronal degeneration.
  • To explore the efficacy of GPR139 agonists against different neurotoxin-induced degeneration pathways relevant to PD research.

Main Methods:

  • Primary mesencephalic cultures were utilized to model DA neurons.
  • Neurodegeneration was induced using 1-methyl-4-phenylpyridinium (MPP+), rotenone, and 6-hydroxydopamine (6-OHDA).
  • The effects of GPR139 agonists and antagonists on neuronal survival were assessed.

Main Results:

  • GPR139 agonists demonstrated concentration-dependent protection of DA neurons against MPP+-induced degeneration in vitro.
  • This protective effect was reversible with a GPR139 antagonist.
  • No significant neuroprotection was observed against rotenone or 6-OHDA mediated DA neuronal degeneration.

Conclusions:

  • GPR139 agonism exhibits specific neuroprotective effects against MPP+-induced dopaminergic neurodegeneration.
  • The findings highlight differential mechanisms of toxicity for common PD modeling agents.
  • GPR139 agonists represent a potential therapeutic strategy for specific neurodegenerative pathways in Parkinson's disease.
Keywords:
G protein-coupled receptorParkinson’s disease modelapoptosiscell-based assaydrug screeningneurodegenerationneuroprotectionneurotoxin

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