Alpha-melanocyte stimulating hormone through melanocortin 4 receptor inhibits iNOS and COX-2 expression in the hypothalamus of male rats.

CARLA CARUSO; CLAUDIA MOHN; ARMANDO L. KARARA; VALERIA RETTORI; HAJIME WATANOBE; HELGI B. SCHIÖTH; ADRIANA SEILICOVICH; MERCEDES LASAGA

NEUROENDOCRINOLOGY

KARGER

Lugar: Basel; Año: 2004 vol. 79 p. 278 - 286

0028-3835

There is evidence that alpha-melanocyte stimulating hormone (a-MSH) has immunomodulatory and anti-inflammatory actions within the brain. In this study, we tested whether these actions are due to inhibition of the synthesis of nitric oxide (NO) and prostaglandins induced by lipopolysaccharide (LPS). Since melanocortin subtype MC4 receptor has been detected in the hypothalamus, we investigated the effect of central administration of a-MSH and HS024 (a selective MC4 receptor antagonist) on the gene expression of inducible, neuronal and endothelial NO synthase (iNOS, nNOS and eNOS) and on cyclooxigenase (COX-1 and COX-2) expression in the mediobasal hypothalamus (MBH) of LPS-treated male Wistar rats.   The peripheral administration of LPS (250 ug/rat, 3h) induced iNOS and COX-2 gene expression in the MBH. This stimulatory effect was reduced by a-MSH (3 nmol/rat) injected 30 min before LPS. a-MSH and HS024 (1 nmol/rat) alone had no effect on iNOS and COX-2 expression. The action of a-MSH on LPS-induced iNOS and COX-2 mRNA levels was not observed in the presence of HS024, suggesting that MC4-R may be involved in the modulatory effect of a-MSH. None of these treatments produced any modifications in nNOS, eNOS and COX-1 expression in MBH.   The increase in serum corticosterone levels induced by LPS was attenuated by a-MSH. Both LPS and a-MSH decreased serum LH and prolactin levels. HS024 failed to modify the inhibitory effects of LPS and a-MSH on prolactin release but reverted the effect of LPS on LH secretion, indicating that MC4-R activation may be involved in the effects of a-MSH on LH secretion in male rats.   When we examined the in vitro effect of LPS (10 ug/ml) and LPS plus Interferon-g (IFN-g, 100 ng/ml) on iNOS expression in MBH, an increase in iNOS mRNA levels was observed only in the presence of LPS + IFN-g. This stimulatory effect was attenuated in the presence of a-MSH (5 uM), which by itself had no effect. No changes were found in nNOS, eNOS, COX-1 or COX-2 expression.   These results indicate that a-MSH reduces the induction of iNOS and COX-2 gene expression at the hypothalamic level during endotoxemia and suggest that endogenous a-MSH may exert an inhibitory tone on iNOS and COX-2 transcription via MC4 receptors acting as a local anti-inflammatory agent within the hypothalamus.