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Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

Authors:	Giuseppe Battaglia Gemma Molinaro Barbara Riozzi Marianna Storto Carla L. Busceti Paola Spinsanti Domenico Bucci Valentina Di Liberto Giuseppina Mudò Corrado Corti Mauro Corsi Ferdinando Nicoletti Natale Belluardo Valeria Bruno

Affiliation:	1. Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.; 2. Department of Human Physiology and Pharmacology, University “LaSapienza”, Rome, Italy.; 3. DIMES, Human Physiology Section, University of Palermo, Palermo,Italy.; 4. Neuroscience Centre of Excellence in Drug Discovery, GlaxoSmithKlineMedicines Research Centre, Verona, Italy.;Tokyo Medical and Dental University, Japan

Abstract:	Metabotropic glutamate (mGlu) receptors have been considered potential targetsfor the therapy of experimental parkinsonism. One hypothetical advantageassociated with the use of mGlu receptor ligands is the lack of the adverseeffects typically induced by ionotropic glutamate receptor antagonists, such assedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.)increased glial cell line-derived neurotrophic factor (GDNF) mRNA and proteinlevels in the mouse brain, as assessed by in situhybridization, real-time PCR, immunoblotting, and immunohistochemistry. Thisincrease was prominent in the striatum, but was also observed in the cerebralcortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNFprotein levels progressively increased from 24 to 72 h following LY379268injection. The action of LY379268 was abrogated by the mGlu2/3 receptorantagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockoutmice, but not in mGlu2 receptor knockout mice. In pure cultures of striatalneurons, the increase in GDNF induced by LY379268 required the activation of themitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, asshown by the use of specific inhibitors of the two pathways. Both invivo and in vitro studies led to the conclusionthat neurons were the only source of GDNF in response to mGlu3 receptoractivation. Remarkably, acute or repeated injections of LY379268 at doses thatenhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protectiveagainst nigro-striatal damage induced by1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed bystereological counting of tyrosine hydroxylase-positive neurons in the parscompacta of the substantia nigra. We speculate that selective mGlu3 receptoragonists or enhancers are potential candidates as neuroprotective agents inParkinson''s disease, and their use might circumvent the limitationsassociated with the administration of exogenous GDNF.

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