Administration Of Luzindole Research Articles

Melatonin Exerts an Anti-Panoptoic Role in Spinal Cord Ischemia-Reperfusion Injured Rats.

Paraplegia is a serious consequence of spinal cord ischemia-reperfusion (SCIR) injury, which leads to neuron death and permanent loss of motor function. However, there is no effective treatment for SCIR. Melatonin exerts a neuroprotective effect in neurodegenerative diseases. However, whether pyroptosis, apoptosis, and necroptosis (PANoptosis) is the primary cause of the massive neural death in SCIR is unknown, and if melatonin exhibits anti-PANoptotic effect in rescuing the disastrous damage is to be decided. This study indicates that melatonin confers neuroprotection in SCIR, attenuating the loss of Nissl body and improving Basso, Beattie & Bresnahan locomotor rating scale scores. Specifically, the apoptotic hallmarks in neurons are increased in SCIR injured spinal cord compared to the sham group. The upregulated trend is reversed by melatonin while the effect of melatonin is abolished by the administration of luzindole, a selective melatonin receptor antagonist. Moreover, similar patterns are found in the necroptotic markers in neurons, the pyroptotic indicators, and the interleukin-1β staining in microglia. In conclusion, PANoptosis may underlie the mass neural death and paraplegia in SCIR, and melatonin confers neuroprotection to the spinal cord via inhibiting PANoptosis.

Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production

BackgroundIt is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection.MethodsVILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated.ResultsRamelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody.ConclusionsOur results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.

Exogenous melatonin reduced blood pressure in late-term ovine fetus via MT1/MT2 receptor pathways

Melatonin is involved in the regulation of blood pressure through the receptor dependent or independent route. However, the effect of melatonin on fetal blood pressure is unknown. This study investigated the effect of melatonin on blood pressure of the late-term ovine fetus in utero. Melatonin and/or antagonists were intravenously administered into the fetuses. Mean arterial pressure and heart rate were recorded. Fetal blood samples were analyzed for biochemical parameters and hormones, including cortisol, angiotensin I, angiotensin II, aldosterone, atrial natriuretic peptide, corticotrophin-releasing hormone, adrenocorticotropic hormone, and endothelin. Fetal blood pressure was decreased following administration of melatonin, whereas it was increased following administration of luzindole, but not prazosin. Plasma level of endothelin was decreased by melatonin, which was blocked by luzindole. Our study suggested that melatonin reduced fetal blood pressure via MT1/MT2 receptors and possibly involving release of endothelin.

HUMULUS LUPULUS (HOPS), IS THERE ANY EVIDENCE FOR CENTRAL NERVOUS EFFECTS RELATED TO SLEEP?

Hops are traditionally used as a mild sedative for anxiety, nervousness, and insomnia even though their sedative and sleep-promoting activities are poorly understood. In vitro experiments of hops extract demonstrated binding activities to serotonin and melatonin receptors. Additionally there are hints that hops extract modulates the γ-aminobutyric acid (GABA) action on the GABA channel. In behavioural tests spontaneous and explorative activity was reduced. In addition, hops extract prolongs the narcotic induced sleeping time indicating a sedation activity. However, the behaviour of small rodents in the plus maze test remains unchanged therefore an anxiolytic action is unlikely. Furthermore hops extract induced a reduction in the body core temperature like melatonin which can be prevented by prior administration of luzindole, a competitive melatonin receptor antagonist. Both of the actions, i.e., sedation and hypothermic action are possibly induced by distinguishable components in the hops extract indicating that there are at least two active principles included in the hops extract. Clinical trials are available for a fixed hops valerian extract combination. Administration in patients suffering from non-organic sleep disturbances showed reduction of sleep latency and wake after sleep onset together with an enlargement of the slow wave sleep. In another study the influence of the fixed extract combination on the prolonged sleep latency was investigated. Valerian alone was not superior to placebo but adding the hops extract, the fixed extract combination was superior to placebo in reduction of the prolonged sleep latency.

Small doses of melatonin increase intestinal motility in rats.

Since melatonin receptors are present in the intestines, the possibility that this hormone may affect intestinal motility has been studied in the rat. Sprague-Dawley male rats were given a carmine cochineal powder meal and were injected intraperitoneally with 1, 10, 100, or 1000 microg/kg melatonin. Sixty minutes after treatment, intestinal transit was found to be faster in animals treated with small doses of melatonin (1 or 10 microg/kg) than in saline-injected controls. This effect, however, appear to be clearly reversed with 100 or 1000 microg/kg melatonin. In fact, these doses of the hormone reduced intestinal transit in rats. The nonselective melatonin receptor antagonist, luzindole (administered intraperitoneally in a dose of 0.25 mg/kg, 15 min prior to melatonin injection) totally prevented the accelerating effect of melatonin (10 microg/kg) on intestinal transit. Luzindole per se failed to affect gut motility. Injection of the reversible acetylcholinesterase inhibitor and cholinergic agent, neostigmine, accelerated intestinal transit but failed to influence melatonin effect on this parameter. In contrast, intraperitoneal injection of the muscarinic receptor antagonist atropine delayed intestinal transit per se but did not reduce the stimulating effect of melatonin on this parameter. Intestinal myoelectrical recording revealed that intestinal myoelectrical activity was increased by intraperitoneal injection of melatonin (10 microg/kg). Administration of luzindole totally prevented melatonin-induced increase of intestinal myoelectrical activity. These results indicate that melatonin may affect intestinal motility in rats when administered in small doses. This effect might be mediated by melatonin receptors in the intestines, although the involvement of central receptors for the hormone is also possible.

Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist.

In addition to marked seasonal changes in reproductive, metabolic, and other physiological functions, many vertebrate species undergo seasonal changes in immune function. Despite growing evidence that photoperiod mediates seasonal changes in immune function, little is known regarding the neuroendocrine mechanisms underlying these changes. Increased immunity in short days is hypothesized to be due to the increase in the duration of nightly melatonin secretion, and recent studies indicate that melatonin acts directly on immune cells to enhance immune parameters. The present study examined the contribution of melatonin receptors in mediating the enhancement of splenocyte proliferation in response to the T cell mitogen Concanavalin A in mice. The administration of luzindole, a high-affinity melatonin receptor antagonist, either in vitro or in vivo significantly attenuated the ability of in vitro melatonin to enhance splenic lymphocyte proliferation during the day or night. In the absence of melatonin or luzindole, splenocyte proliferation was intrinsically higher during the night than during the day. In the absence of melatonin administration, luzindole reduced the ability of spleen cells to proliferate during the night, when endogenous melatonin concentrations are naturally high. This effect was not observed during the day, when melatonin concentrations are low. Taken together, these results suggest that melatonin enhancement of splenocyte proliferation is mediated directly by melatonin receptors on splenocytes and that there is diurnal variation in splenocyte proliferation in mice that is also mediated by splenic melatonin receptors.