Central Interleukin-1ß Suppresses the Nocturnal Secretion of Melatonin.

In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer's disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1ß in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1ß on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1ß (50 µg/animal) suppressed (P < 0.05) nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased (P < 0.05) synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1ß also inhibited (P < 0.05) the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1ß to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1ß in the aetiology of disruptions in melatonin secretion.

Interleukin-1 ß Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study.

The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1ß, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1ß (75 pg/mL), or (4) NE + IL-1ß. It was found that IL-1ß abolished (P < 0.05) NE-induced increase in melatonin release. Treatment with IL-1ß also reduced (P < 0.05) expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1ß treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated (P < 0.05) expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1ß suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression.

Influence of fundectomy and intraperitoneal or intragastric administration of apelin on apoptosis, mitosis, and DNA repair enzyme OGG1,2 expression in adult rats gastrointestinal tract and pancreas.

Apelin, endogenous ligand of G protein-coupled apelin receptor (APJ), is released into the gastrointestinal lumen, however, local effect of luminal apelin on gut epithelium has not been elucidated so far. The present study aimed to determine the effects of fundectomy, and intraperitoneal or intragastric administration of apelin on pancreatic, gastric and intestinal epithelium apoptosis, mitosis and DNA repair enzyme OGG1,2 expression in adult Wistar rats. Apelin-13 was given by intraperitoneal or gastric gavage twice a day for 10 days (100 nmol/kg b. wt./day). Fundectomized rats did not receive apelin. Control groups received saline as placebo. At the end of the experiment the rats were sacrificed and the pancreas, gastric fundus, duodenum, middle jejunum and colon tissue samples were harvested for immunofluorescence studies. Intraperitoneal and intragastric apelin-13 reduced apoptosis, mitosis and number of DNA damages in rats gastrointestinal tract (p≤0.001) as compared to control. In fundectomized rats, the apoptotic index in the pancreas and colon was decreased (p<0.001), and in the stomach and jejunum was increased (p<0.001). Mitotic index was decreased in all gastrointestinal tissues. Number of DNA damages (p≤0.001) in fundectomized rats was reduced except stomach where OGG1,2 expression was increased (p≤0.001) as compared to control. In conclusion, circulating and luminal exogenous apelin-13 caused similar effects on intestinal epithelium. Endogenous (gastric) apelin is important for renewal of intestinal epithelium in adult rats. Pharmacological doses of apelin-13 may reduce the cell turnover in the upper gastrointestinal tract epithelium and pancreas, and improve the overall gut health.

The effect of rivastigmine on the LPS-induced suppression of GnRH/LH secretion during the follicular phase of the estrous cycle in ewes.

This study was designed to determine the effect of a potent subcutaneously injected acetylcholinesterase inhibitor, rivastigmine (6mg/animal), on the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release during inflammation induced by an intravenous lipopolysaccharide (LPS) (400ng/kg) injection in ewes during the follicular phase of the estrous cycle. The results are expressed as the mean values from -2 to -0.5h before and +1 to +3h after treatment. Rivastigmine decreased the acetylcholinesterase concentration in the blood plasma from 176.9±9.5 to 99.3±15.1µmol/min/ml. Endotoxin suppressed LH (5.4±0.6ng/ml) and GnRH (4.6±0.4pg/ml) release; however, the rivastigmine injection restored the LH concentration (7.8±0.8ng/ml) to the control value (7.8±0.7ng/ml) and stimulated GnRH release (7.6±0.8pg/ml) compared to the control (5.9±0.4pg/ml). Immune stress decreased expression of the GnRH gene and its receptor (GnRH-R) in the median eminence as well as LHß and GnRH-R in the pituitary. In the case of the GnRH and LHß genes, the suppressive effect of inflammation was negated by rivastigmine. LPS stimulated cortisol and prolactin release (71.1±14.7 and 217.1±8.0ng/ml) compared to the control group (9.0±5.4 and 21.3±3.5ng/ml). Rivastigmine also showed a moderating effect on cortisol and prolactin secretion (43.1±13.1 and 169.7±29.5ng/ml). The present study shows that LPS-induced decreases in GnRH and LH can be reduced by the AChE inhibitor. This action of the AChE inhibitor could result from the suppression of pro-inflammatory cytokine release and the attenuation of the stress response. However, a direct stimulatory effect of ACh on GnRH/LH secretion should also be considered.

The effect of exogenous apelin on the secretion of pancreatic juice in anaesthetized rats.

Apelin is known to stimulate cholecystokinin (CCK) and inhibit insulin release, however the mechanisms on pancreatic secretion remain unclear. The present study aimed to determine the expression of apelin and apelin receptor in the pancreas by immunofluorescence studies and the effect of exogenous apelin on the secretion of pancreatic juice in anesthetized rats. Pancreatic-biliary juice (P-BJ) was collected from Wistar rats treated with apelin (10, 20 and 50 nmol/kg b.w., boluses given every 30 min intravenously or intraduodenaly). The same apelin doses were administered to rats subjected to intraduodenal tarazapide, capsaicin or vagotomy. Pancreatic blood flow was measured by a laser doppler flowmeter. Direct effects of apelin were tested on dispersed acinar cells. Apelin receptor was expressed on acinar cells, pancreatic duct and islets cells, whereas apelin in pancreatic acini, but not in the islets. Intravenous apelin decreased P-BJ volume, protein and trypsin outputs in a dose-dependent manner. In contrast, intraduodenal apelin stimulated P-BJ secretion. Pharmacological block of mucosal CCK(1) receptor by tarazepide, vagotomy and capsaicin pretreatment abolished the effects of intravenous and intraduodenal apelin on P-BJ volume, protein and tryspin outputs. Apelin decreased the pancreatic blood flow. Apelin at 10(-6) M increased the release of amylase from non-stimulated and CCK-8-stimulated acinar cells. In conclusion, apelin can affect the exocrine pancreas through a complex mechanism involving local blood flow regulation and is driven by vagal nerves.