Abstract
Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.
Highlights
Metabotropic glutamate receptors have been considered potential targets for neuroprotective drugs since the early times of their characterization
It is the mGlu2 receptor that mediates the antipsychotic activity of mGlu2/3 receptor agonists [33,35,36], while the mGlu3 receptor is still in search of a function that can be relevant for human studies
There are a number of potential explanations for the lack of activity of high doses of LY39268, which include the recruitment of additional Metabotropic glutamate (mGlu) receptor subtypes, such as mGlu2 and mGlu8 receptors [39], the recruitment of additional intracellular pathways that negatively regulate the transcriptional machinery of the glial cell line-derived neurotrophic factor (GDNF) gene, or the development of tachyphylaxis
Summary
Metabotropic glutamate (mGlu) receptors have been considered potential targets for neuroprotective drugs since the early times of their characterization. PLoS ONE | www.plosone.org mGlu Receptors and GDNF [13,16,17,18,19,20,21] Along this line, we decided to study whether activation of group-II mGlu receptors influences the endogenous production of glial cell line-derived neurotrophic factor (GDNF), which is a potent factor for survival and axonal growth of mesencephalic dopaminergic neurons and has been shown to improve motor symptoms and attenuate nigro-striatal damage in experimental animal models of parkinsonism [22,23,24,25,26]. We report that selective pharmacological activation of mGlu receptors enhances the production of GDNF in mouse striatum, and that the potent mGlu2/3 receptor agonist, LY379268, is highly protective in the MPTP model of parkinsonism at doses that up-regulate GDNF
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