-melanocyte stimulating hormone (-MSH) exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western Blot analysis.

-MSH (5 µM) reduced bacterial lipopolysaccharide (LPS, 1 µg/ml) + Interferon- (IFN-, 50 ng/ml) induced nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) in cultured astrocytes after 24 h. -MSH also attenuated the stimulatory effect of LPS/IFN- on prostaglandin E₂ release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the anti-inflammatory effects of -MSH, suggesting a MC4R mediated mechanism in the action of this melanocortin.

In astrocytes, LPS/IFN- treatment reduced cell viability, increased the number of TUNEL-positive cells and activated caspase-3. -MSH prevented these apoptotic events and this cytoprotective effect was abolished by HS024. LPS/IFN- decreased Bcl-2 whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. -MSH produced a shift in Bax/Bcl-2 ratio towards astrocyte survival since it increased per se Bcl-2 expression and also prevented the effect of LPS/IFN- on Bax and Bcl-2 expression.

In summary, these findings suggest that -MSH, through MC4R activation, attenuates LPS/IFN--induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN--induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.