The endogenous feeding suppressant, 2-buten-4-olide, impairs the pulsatile secretion of luteinizing hormone through endogenous opioid peptides

Abstract

Objective: To clarify the mechanism of the suppressive effect of 2-buten-4-olide (2-B4O), an endogenous feeding suppressant, on the pulsatile secretion of luteinizing hormone (LH), by studying whether endogenous opioid peptides are involved in this suppressive effect. Methods: Using ovariectomized (ovx) rats, blood samples were taken every 6 min for 2 h after administration of 2-B4O or saline into the third cerebroventricle (3V) and sequential i.v. injection of naloxone (0.5 mg/kg per h) or saline. Rats were divided into three experimental groups: group 1: 3V saline þ i.v. saline (control); group 2: 3V 2-B4O þ i.v. saline; group 3: 3V 2-B4O+i.v. naloxone. Serum LH concentrations were determined by double-antibody RIA. To determine whether 2-B4O affected the biosynthetic activity of the opioidergic neurons within the ovx rat arcuate nucleus, we measured the concentrations of pro-opiomelanocortin (POMC) mRNA, a precursor of b-endorphin, in the rostral arcuate nucleus using non-radioactive in situ hybridization and a computerized image-analysis system. Results: 2-B4O significantly suppressed the pulse frequency of LH (group 2: 1.5 Ϯ 0.33 pulses/2 h, group 1: 2.43 Ϯ 0.2 pulses/2 h; P < 0.05), but naloxone blocked its suppressive effect and restored the pulse frequency (group 3: 3.29 Ϯ 0.36 pulses/2 h, group 2: 1.5 Ϯ 0.33 pulses/2 h; P < 0.01). There were no significant changes in the mean LH concentrations and amplitude. Furthermore, 2-B4O significantly stimulated the expression of POMC mRNA in the rostral arcuate nucleus. Conclusion: These results suggest that 2-B4O may impair the pulsatile secretion of LH by activating the opioid pathway within the hypothalamus.

Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats

“…injections of GnRH inhibiting factors such as hypocretin (HCRT; also known as orexin) and 2-buten-4-olide suppressed plasma LH levels immediately after injection, with the suppression being sustained for at least 1 h (Saito et al 1993, Kaji et al 1998, Tamura et al 1999, Iwasa et al 2007). Kriegsfeld et al (2006) deduced that RFRP-3 suppresses LH secretion at the hypothalamic level, as more than 40% of the GnRH neurons were projected from the GnIH-immunoreactive fibers.…”

Hypothalamic Ghrelin Suppresses Pulsatile Secretion of Luteinizing Hormone via β-Endorphin in Ovariectomized Rats

“…Previous reports [9,13,14] and the present report have shown that ghrelin is one of the inhibitory factors underlying pulsatile secretion of LH. Other than ghrelin, we have previously reported that 2-B4O, a short-chain organic acid that appears in blood in a fasted state, suppressed pulsatile secretion of LH when administered intracerebroventricularly in ovariectomized rats [15], with this effect negated by simultaneous administration of NAL [17]. Intracerebroventricular administration of 2-B4O also significantly increased expression levels of pro-opiomelanocortin (POMC) mRNA-positive cells in the ARC [17].…”

“…After each sampling, the blood was replaced by an equal volume of heparinized saline containing NAL (Sigma Chemical, St. Louis, Mo., USA; 0.5 mg/kg/h), as a specific opioid antagonist, or heparinized saline only. In this experiment, NAL was administrated intermittently using the sampling cannula at the time of each sampling, because it was difficult to insert another route for continuously intravenous administration of NAL besides the collecting cannula [16,17]. …”

“…We have reported that orexin [8] and 2-buten-4-olide (2-B4O) [15] suppress the pulsatile secretion of LH in ovariectomized female rats and that β-END was involved in these effects [16,17]. Recent findings have suggested that β-END is involved in the inhibitory effects of ghrelin on pulsatile secretion of LH in healthy men [14].…”

QSAR studies on structurally similar 2-arylidene-4-(4-phenoxy -phenyl) but-3-en-4-olides as anti-inflammatory agents

“…The butenolides are also reported to have protein tyrosine phosphates (CDC 25) inhibitory and endogenous feeding suppressant activities. 9,10 Recently Husain et al reported a series of butenolides with anti-inflammatory potential. 11 physicochemical properties and biological activities in chemical, environmental and pharmaceutical areas.…”