Reduced cAMP levels, Akt activation and p65-c-Rel dimerization: mechanisms involved in the protective effects of mGluR3 agonists in cultured astrocytes

DANIELA DURAND; LILA CARNIGLIA; CARLA CARUSO; MERCEDES LASAGA

Taormina

Congreso; 7th International Meeting on Metabotropic Glutamate Receptors; 2011

In recent decades, astrocytes have emerged as key pieces in the maintenance of normal functioning of the central nervous system. Any impairment in astroglial function can ultimately lead to generalized disturbance in the brain, thus pharmacological targets associated with prevention of astrocyte death are actually promising. Subtype 3 of metabotropic glutamate receptors (mGluR3) is present in astrocytes, its activation exerting neuroprotective roles. In fact, we have previously demonstrated that mGluR3 selective agonists prevent nitric oxide (NO)-induced astrocyte death [1]. However, mechanisms responsible for that cytoprotective property are still subject to study. Although inhibition of adenylyl cyclase by mGluR3 activation was extensively reported, the involvement of reduced cAMP levels in the effects of mGluR3 agonists and the association between cAMP decrease and the downstream pathways activated by mGluR3 remain neglected. Thus, we studied intracellular signaling mediating anti-apoptotic actions of mGluR3 in cultured rat astrocytes exposed to NO. We showed by the MTT method that both a non-hydrolyzable analog of cAMP, dibutyryl-cAMP (1 mM), and an Akt1/2 inhibitor (0.5 M) abolished the anti-apoptotic effect of the mGluR3 agonists LY379268 or LY404039 (100 M) on cultured astrocytes exposed to 1 mM NO (p