Reduced cAMP levels and Akt activation are implicated in the anti-apoptotic actions of mGluR3 agonists in astrocytes.

DURAND DANIELA; CARNIGLIA LILA; CARUSO CARLA; LASAGA MERCEDES

Huerta Grande, Córdoba

Congreso; Segunda Reunión Conjunta de la Sociedad Argentina de Neurociencias y el Taller Argentino de Neurociencias; 2010

SAN

Metabotropic glutamate receptors (mGluR) are implicated in neuroplasticity and neuroprotection. We have previously shown that mGluR3 activation prevents NO-induced astrocyte death, by modulating levels of apoptotic mitochondrial pathway mediators. Since mGluR3 activation inhibits adenylate cyclase and induces Akt activation, we studied these pathways. A non-hydrolyzable analog of cAMP, dibutyryl-cAMP and an Akt1/2 inhibitor both abolished the anti-apoptotic effect of the mGluR3 agonists LY379268 or LY404039 on cultured astrocytes exposed to NO (p0.001 vs. NO+LY). However, a cGMP analog, 8Br-cGMP, did not modify the effect of LY379268 on cell viability. NF-kB family proteins mediate inflammatory responses and survival signaling. Opposite to p65-p50, c-Rel containing dimers promote transcription of anti-apoptotic genes. We determined nuclear p65-c-Rel levels by coimmunoprecipitation. The treatment of astrocytes with LY379268 for 30 min induced nuclear p65-c-Rel interaction (p0.05) and it did not change p65-c-Rel levels induced by LPS+IFN-gamma, suggesting that c-Rel-containing dimers could be implicated in the protective role of mGluR3 in astrocytes. Our results indicate that mGluR3 activation may exert its neuroprotective role on astrocyte degeneration through reduction in cAMP levels, Akt activation and possibly c-Rel activation.