title: mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum.
abstract: In the present study we aimed to verify if the enhancement of glial cell line-derived neurotrophic factor (GDNF) production in mouse striatum following treatment with LY379268 may also induce in the nigrostriatal system a time-related activation of RET receptor and its specific intracellular signaling. For this purpose, we have investigated the effects of LY379268 treatment on RET phosphorylation at the Tyr1062 and on downstream signaling Erk1/2, Akt and PLCγ1 pathway activation. The results showed that treatment with LY379268 (3 mg/kg) induces a significant increase of GDNF levels and time-related RET and Erk1/2 phosphorylation in the striatum. These increases were detected at 24 h and 48 h following LY379268 treatment. No changes were observed in the Akt and PLCγ1 phosphorylation levels. Similar results for p-Erk1/2 were observed in the substantia nigra. A complete block of LY379268 effect on striatal RET and p-Erk1/2 phosphorylation was observed in mice intrastriatal injected with anti-GDNF antibodies, suggesting a correlation between GDNF upregulation and RET activation. Overall, with present data we have shown that activation of mGluR2/3 receptors by LY379268 may be particularly promising for nigrostriatal dopaminergic system protection by enhancing striatal levels of GDNF/RET trophic system activity.
authors.affiliation: Department of Experimental Medicine and Clinical Neuroscience, University of Palermo, Palermo, Italy. v.diliberto@unipa.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Liberto
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Mudò
authors.forename: Natale
authors.initials: N
authors.lastname: Belluardo
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000502:physiology; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D048052:Mitogen-Activated Protein Kinase 3