PROTECTIVE ACTIONS OF GROUP II METABOTROPIC GLUTAMATE RECEPTORS IN CULTURED RAT ASTROCYTES

D. DURAND; L. CARNIGLIA; C. CARUSO; M. LASAGA

Huerta Grande, Cordoba

Congreso; I Reunion Conjunta de Neurociencias; 2009

Sociedad Argentina de Investigación en Neurociencias

Metabotropic glutamate receptors (mGluR) are implicated in neuroplasticity and neuroprotection. In the present assay, we investigated the effect of group II mGluR on cell death and NF-kB activation in cultured rat astrocytes treated with LPS+IFN-gamma and analyzed the expression of these receptors after such inflammatory stimulus. Treatment with LPS (1 µg/ml)+IFN-gamma (50 ng/ml) for 24 h augmented the percentage of TUNEL-positive astrocytes (p<0.01). In the presence of a selective agonist of group II mGluR (LY379268 100 µM) this effect was abrogated (p<0.05). The mGluR antagonist EGLU (300 mM) reverted the effect of LY379268 (p<0.001). An inhibitor of NO synthesis, NMMA (1 mM), reduced almost completely the percentage of apoptotic cells increased by LPS+IFN-gamma (p<0.001), suggesting that NO is the major mediator of LPS+IFN-gamma-evoked astrocyte death. Since NF-kB mediates inflammatory responses and survival signaling, we determined its translocation to the nucleus and the expression of its inhibitor IkB. Exposure to LPS+IFN-gamma for 30 min incremented the NF-kB protein levels in the nuclear fraction (p<0.05). No significant changes were observed in the presence of LY379268. However, cytosolic IkB levels were significantly reduced by LPS+IFN-gamma (p<0.01) whereas LY379268 reverted this effect. Protein expression of group II mGluR was induced by LPS+IFN-gamma (p<0.05), whereas exposure of astrocytes to LY379268 significantly reduced their expression (p<0.05), suggesting the involvement of auto-regulatory mechanisms in the control of mGluR activity.Our results indicate that selective activation of group II mGluR could play a neuroprotective role on inflammatory processes in the CNS, by preventing astrocyte degeneration