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

Kirsten Bayer Andersen; Jens Leander Johansen; Morten Hentzer; Garrick Paul Smith; Gunnar P H Dietz

doi:10.3389/fncel.2016.00164

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

Front Cell Neurosci. 2016 Jun 28:10:164. doi: 10.3389/fncel.2016.00164. eCollection 2016.

Authors

Kirsten Bayer Andersen¹, Jens Leander Johansen¹, Morten Hentzer², Garrick Paul Smith³, Gunnar P H Dietz¹

Affiliations

¹ Department of Neurodegeneration, H. Lundbeck A/S Valby, Denmark.
² Department of Molecular Screening, H. Lundbeck A/S Valby, Denmark.
³ Department of Discovery Chemistry 2, H. Lundbeck A/S Valby, Denmark.

Abstract

The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson's disease (PD) models and potential for GPR139 agonists in neuroprotection.

Keywords: G protein-coupled receptor; Parkinson’s disease model; apoptosis; cell-based assay; drug screening; neurodegeneration; neuroprotection; neurotoxin.