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Molecular Signalling Mediating the Protective Effect of A₁ Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes

Department. of Biomedical Sciences, "G. D'Annunzio" University, Chieti, Italy (R.C., I.D.A., P.B., M.D.A., E.N., S.B., P.D.I., F.C.); and Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Rome, Italy, and Department of Neuropharmacology, I.N.M. Neuromed, Pozzilli, Italy (V.B., F.N.)

Astrocyte death may occur in neurodegenerative disorders and complicates the outcome of brain ischemia, a condition associated with high extracellular levels of adenosine and glutamate. We show that pharmacological activation of A₁ adenosine and mGlu3 metabotropic glutamate receptors with N⁶-chlorocyclopentyladenosine (CCPA) and (–)2-oxa-4-aminocyclo-[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), respectively, protects cultured astrocytes against apoptosis induced by a 3-h exposure to oxygen/glucose deprivation (OGD). Protection by CCPA and LY379268 was less than additive and was abrogated by receptor blockade with selective competitive antagonists or pertussis toxin. Both in control astrocytes and in astrocytes exposed to OGD, CCPA and LY379268 induced a rapid activation of the phosphatidylinositol-3-kinase (PI3K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2)/mitogen-activated protein kinase (MAPK) pathways, which are known to support cell survival. In cultures exposed to OGD, CCPA and LY379268 reduced the activation of c-Jun N-terminal kinase and p38/MAPK, reduced the levels of the proapoptotic protein Bad, increased the levels of the antiapoptotic protein Bcl-X_L, and were highly protective against apoptotic death, as shown by nuclear 4'-6-diamidino-2-phenylindole staining and measurements of caspase-3 activity. All of these effects were attenuated by treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), which inhibit the MAPK and the PI3K pathways, respectively. These data suggest that pharmacological activation of A₁ and mGlu3 receptors protects astrocytes against hypoxic/ischemic damage by stimulating the PI3K and ERK1/2 MAPK pathways.

Address correspondence to: Dr. Renata Ciccarelli, Department of Biomedical Sciences, Section of Pharmacology, University of Chieti, Medical School, Via dei Vestini 29, pal. B, 66013 Chieti, Italy. E-mail: r.ciccarelli{at}dsb.unich.it