Alpha-Melanocyte-Stimulating Hormone through Melanocortin-4 Receptor Inhibits Nitric Oxide Synthase and Cyclooxygenase Expression in the Hypothalamus of Male Rats

Abstract

There is evidence that α-melanocyte-stimulating hormone (α-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 α-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 cyclooxygenase (COX-1 and COX-2) expression in the mediobasal hypothalamus (MBH) of LPS-treated male Wistar rats. Peripheral administration of LPS (250 µg/rat, 3 h) induced iNOS and COX-2 gene expression in the MBH. This stimulatory effect was reduced by α-MSH (3 nmol/rat) injected 30 min before LPS. α-MSH and HS024 (1 nmol/rat) alone had no effect on iNOS and COX-2 expression. The action of α-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 α-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 α-MSH. Both LPS and α-MSH decreased serum LH and prolactin levels. HS024 failed to modify the inhibitory effects of LPS and α-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 α-MSH on LH secretion in male rats. When we examined the in vitro effect of LPS (10 µg/ml) and LPS plus interferon-γ (IFN-γ, 100 ng/ml) on iNOS expression in MBH, an increase in iNOS mRNA levels was observed only in the presence of LPS + IFN-γ. This stimulatory effect was attenuated in the presence of α-MSH (5 µM), which by itself had no effect. No changes were found in nNOS, eNOS, COX-1 or COX-2 expression. These results indicate that α-MSH reduces the induction of iNOS and COX-2 gene expression at the hypothalamic level during endotoxemia and suggest that endogenous α-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.

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway

“…Finally, ␣-MSH-induced inhibition of pro-inflammatory NFB/COX-2 pathway is involved in the antineoplastic mechanism of POMC gene delivery. Similar ␣-MSH-induced inhibition of NFB/COX-2 activities has been reported in hypothalamus of lipopolysaccharide-treated rats via melanocortin 4 receptor (Caruso et al, 2004). Because of its potent suppression of melanoma progression in either the chemoprevention study using engineered melanoma cells or therapeutic study with established tumors, POMC gene delivery may constitute a novel chemoprevention or treatment modality for melanoma.…”

Role of Nitric Oxide in α-Melanocyte-Stimulating Hormone-Induced Hypotension in the Nucleus Tractus Solitarii of the Spontaneously Hypertensive Rats

“…Besides, the mRNA levels and the activities of iNOS in liver and lung were decreased by central injection of ␣-MSH (Catania et al, 1999). During endotoxemia, ␣-MSH reduces the induction of iNOS and cyclooxygenase-2 gene expression at the hypothalamic level and suggests that endogenous ␣-MSH may exert an inhibitory tone on iNOS and cyclooxygenase-2 transcription via MC-4R acting as a local anti-inflammatory agent within the hypothalamus (Caruso et al, 2004). In contrast, there are reports supporting that ␣-MSH treatment stimulates the NO production in vitro and in vivo.…”

“…Central ␣-MSH administration may differentially regulate the endogenous iNOS expression and activities, thereby altering the NO production in various cellular or animal models. Cumulative evidence indicates that ␣-MSH treatment down-regulates the iNOS expression and activities (Star et al, 1995;Catania et al, 1999;Mandrika et al, 2001;Caruso et al, 2004). In peripheral tissues during endotoxin-induced sepsis, injection of ␣-MSH inhibited the production and release of NO from macrophages (Star et al, 1995;Mandrika et al, 2001).…”

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

“…a-Melanocyte-stimulating hormone is known to inhibit COX-2 expression after endotoxin-induced inflammation. 32,33 Therefore, a-MSH gene therapy might exert antihepatic fibrogenesis through COX-2 modulation.…”