Intraventricular administration of antivasopressin serum inhibits retention in mice

Elevations and decrements in the levels of the posterior pituitary hormone vasopressin result in facilitations and deficits in retention, respectively, in rats. Despite the frequent use of mice in studies of pharmacological influences on retention, there is a paucity of information regarding the role of endogenous peptides, particularly vasopressin, in the memory processes of mice. In the present experiment, mice suffering from acute inactivation of central vasopressin, induced by an immediately posttraining, 2 microliters, intracerebroventricular injection of antivasopressin serum, displayed a retention deficit for passive avoidance training. The results of this experiment suggest that endogenous vasopressin modulates the memory processes of mice, as well as rats.     

UCP2 protects hypothalamic cells from TNF-alpha-induced damage

Uncoupling protein 2 (UCP2) is highly expressed in the hypothalamus; however, little is known about the functions it exerts in this part of the brain. Here, we hypothesized that UCP2 protects hypothalamic cells from oxidative and pro-apoptotic damage generated by inflammatory stimuli. Intracerebroventricular injection of tumor necrosis factor alpha (TNF-alpha)-induced an increase of UCP2 expression in the hypothalamus, which was accompanied by increased expression of markers of oxidative stress and pro-apoptotic proteins. The inhibition of UCP2 expression by an antisense oligonucleotide enhanced the damaging effects of TNF-alpha. Conversely, increasing the hypothalamic expression of UCP2 by cold exposure reversed most of the effects of the cytokine. Thus, UCP2 acts as a protective factor against cellular damage induced by an inflammatory stimulus in the hypothalamus.     

Hypothalamic lipotoxicity and the metabolic syndrome

Ectopic accumulation of lipids in peripheral tissues, such as pancreatic β cells, liver, heart and skeletal muscle, leads to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. Current evidence has demonstrated that hypothalamic sensing of circulating lipids and modulation of hypothalamic endogenous fatty acid and lipid metabolism are two bona fide mechanisms modulating energy homeostasis at the whole body level. Key enzymes, such as AMP-activated protein kinase (AMPK) and fatty acid synthase (FAS), as well as intermediate metabolites, such as malonyl-CoA and long-chain fatty acids-CoA (LCFAs-CoA), play a major role in this neuronal network, integrating peripheral signals with classical neuropeptide-based mechanisms. However, one key question to be addressed is whether impairment of lipid metabolism and accumulation of specific lipid species in the hypothalamus, leading to lipotoxicity, have deleterious effects on hypothalamic neurons. In this review, we summarize what is known about hypothalamic lipid metabolism with focus on the events associated to lipotoxicity, such as endoplasmic reticulum (ER) stress in the hypothalamus. A better understanding of these molecular mechanisms will help to identify new drug targets for the treatment of obesity and metabolic syndrome.     

Anti-allodynic effects of intrathecally and intracerebroventricularly administered 26RFa, an intrinsic agonist for GRP103, in the rat partial sciatic nerve ligation model

26RFa and QRFP are endogenous ligands of GPR103. 26RFa binding sites are widely distributed in the brain and the spinal cord where they are involved in processing pain. In the present study, the effects of intrathecal and intracerebroventricular applications of 26RFa on the level of mechanical allodynia induced by partial sciatic nerve ligation were examined in rats. The level of mechanical allodynia was measured using von Frey filaments. Intrathecal and intracerebroventricular injection of 26RFa attenuated the level of mechanical allodynia. 26RFa has been reported to activate not only GPR103 but also neuropeptide FF2 receptor and the effect of intrathecally and intracerebroventricularly administered 26RFa was not antagonized by BIBP3226, an antagonist of neuropeptide FF receptor. Immunohistochemical examination revealed that QRFP-like immunoreactivity (QRFP-LI) was expressed mainly in the small to medium sized neurons in the L5 dorsal root ganglion (DRG) and that partial sciatic nerve injury increased the percentage of QRFP-LI positive neurons. 7 days after the nerve injury, QRFP-LI positive neurons in the L5 DRG ipsilateral to the partial sciatic nerve injury were larger than those in the L5 DRG ipsilateral to the sham operation. These data suggest that (1) exogenously applied 26RFa modulates nociceptive transmission at the spinal and the supraspinal brain in the neuropathic pain model, (2) the mechanism 26RFa uses to produce an anti-allodynic effect may be mediated by the activation of GPR103, and (3) partial sciatic nerve ligation affects the expression of QRFP-LI in the dorsal root ganglion.     

LY226936 Administered Orally and Centrally to Obese Zucker Rats Suppresses Food Intake and Body Weight Gain

LY226936, methylcarbamothoic acid-S-(4,5-dihydro-2-thiazolyl) ester, is a new compound that, when administered to obese Zucker rats, caused reduced food intake. LY226936 reduced the food consumption after a single oral dose of 50 and 100 mg/kg. On chronic oral administration to meal-fed obese (5 to 35 mg/kg. once daily) and to fed obese and lean (15 mg/kg. twice daily) Zucker rats, LY226936 reduced food intake and body weight gain for periods ranging from 40 to 48 days. The effect on both parameters was statistically significant. There is no evidence in our studies that tolerance to the actions of LY226936 developed. LY226936 decreased the consumption of both high carbohydrate and high fat diets. Food consumption of meal-fed obese Zucker rats was reduced significantly each time a single dose of 10 ugm LY226936 per rat was infused intracerebroventricularly. None of the receptors studied (mu and kappa opioid, CCK, serotonin, neuropeptide Y, galinin, N-methyl-D-aspartic acid) appeared to bind LY226936 and therefore, appear not to be involved in the depression of food intake by the obese Zucker rat.     

Inhibitory effect of chicken gonadotropin-releasing hormone II on food intake in the goldfish, Carassius auratus

Gonadotropin-releasing hormone (GnRH) is an evolutionarily conserved neuropeptide with 10 amino acid residues, which possesses some structural variants. A molecular form known as chicken GnRH II ([His⁵ Trp⁷ Tyr⁸] GnRH, cGnRH II) is widely distributed in vertebrates, and has recently been implicated in the regulation of sexual behavior and food intake in an insectivore, the musk shrew. However, the influence of cGnRH II on feeding behavior has not yet been studied in model animals such as rodents and teleost fish. In this study, therefore, we investigated the role of cGnRH II in the regulation of feeding behavior in the goldfish, and examined its involvement in food intake after intracerebroventricular (ICV) administration. ICV-injected cGnRH II at graded doses, from 0.1 to 10 pmol/g body weight (BW), induced a decrease of food consumption in a dose-dependent manner during 60 min after treatment. Cumulative food intake was significantly decreased by ICV injection of cGnRH II at doses of 1 and 10 pmol/g BW during the 60-min post-treatment observation period. ICV injection of salmon GnRH ([Trp⁷ Leu⁸] GnRH, sGnRH) at doses of 0.1-10 pmol/g BW did not affect food intake. The anorexigenic action of cGnRH II was completely blocked by treatment with the GnRH type I receptor antagonist, Antide. However, the anorexigenic action of cGnRH II was not inhibited by treatment with the corticotropin-releasing hormone (CRH) 1/2 receptor antagonist, α-helical CRH₍₉₋₄₁₎, and the melanocortin 4 receptor antagonist, HS024. These results suggest that, in the goldfish, cGnRH II, but not sGnRH, acts as an anorexigenic factor, as is the case in the musk shrew, and that the anorexigenic action of cGnRH II is independent of CRH- and melanocortin-signaling pathways.     

Consummatory behavior and metabolic indicators after central ghrelin injections in rats

Ghrelin, an endogenous ligand for the growth-hormone-secretagogue receptor, is a 28-amino acid peptide with a post-translational acyl modification necessary for its activity. It has central nervous system actions that affect appetite, body mass and energy balance. An intracerebroventricular (ICV) injection protocol of sub-nanomolar doses of ghrelin, known to alter the morphology of ACTH and GH producing pituicytes and plasma levels of these hormones, was used to provide an overview of metabolic changes linked to energy metabolism. Variables measured were: food intake (FI), water intake (WI), fecal mass, urine volume, body weight (BW), retroperitoneal (RP) and epididymal (EPI) white adipose tissue (WAT), and changes in serum leptin, insulin, triglycerides, cholesterol, and glucose. Five injections of rat ghrelin or PBS (n = 8 per group) were given ICV every 24 h (1 μg/5 μL PBS) to adult male rats. Ghrelin had a positive and cumulative effect on FI, WI and BW (p < 0.05), but not feces mass or urine volume (p > 0.05). Centrally applied ghrelin clearly increased RP WAT (by 235%, p < 0.001), EPI WAT (by 85%, p < 0.05) and serum insulin levels (by 43%, p < 0.05), and decreased serum leptin levels (by 77%, p < 0.05) without (p > 0.05) evoking changes in blood triglyceride cholesterol, or glucose levels.

These data and the available literature clearly document that exposure of the brain of normal rats, over time, to sub-nanomolar doses of ghrelin results in metabolic dysregulation culminating in increased body mass, consummatory behavior, and lipid stores as well as changes in blood leptin/insulin levels. Thus, modulation of central ghrelin receptors may represent a pharmacological approach for controlling multiple factors involved in energy balance and obesity.     

Action of anorexigenic peptide injected into the brain: Dissociation of effect on body weight and feeding in the rat

Previous reports on the effect of anorexigenic peptide (AXP) administered systemically in the rodent are inconsistent in terms of the effect of the tri-peptide on food intake and body weight. The purpose of this study was to examine the effect of AXP infused into the brain on these measures. In post-pubescent female rats of the Sprague-Dawley strain, guide cannulae were permanently implanted in the lateral cerebral ventricle for repeated intracerebroventricular (ICV) infusion. Postoperatively, measures of food and water intake and body weight were obtained every day at the same time. After a 7-day base-line period, AXP was infused bilaterally in a total volume of 15 μl and in a dose of either 0.25 μg (n=7) or 1.25 μg (n=5), with artificial CSF vehicle serving as the control solution (n=6). ICV infusions were given once daily for 20 consecutive days, after which the same intake and body weight measures were recorded for another 7-day period. The rats given 0.25 μg AXP showed a significant suppression in weight gain with the overall slope of the growth curve being 0.358. In contrast, the growth slope of the rats given the 1.25 μg dose of AXP was 0.621, whereas those given the CSF was 0.823. Although the trends of intake of food tended to follow the curves of the rats' body weight, the difference between g/kg food intake of rats during ICV infusions of either dose of AXP was not significantly different from that of the CSF controls. Water intake also was unaffected by either dose of AXP. These results demonstrate that this tri-peptide derived from urine of patients afflicted with anorexia nervosa exerts a direct effect on the brain. Since the 0.25 μg dose of AXP infused acutely ICV caused a sustained hyperthermia, its mechanism of action is apparently a metabolic one; that is, the interruption in the gain in body weight of the rat is independent of the amount of food it ingests.     

The effects of bicuculline and muscimol on glutamate-induced feeding behavior in broiler cockerels

This study was designed to examine the effects of intracerebroventricular (ICV) injection of bicuculline (GABA_A receptor antagonist) and muscimol (GABA_A receptor agonist) on glutamate-induced eating response in 24-h food-deprived (FD24) broiler cockerels. At first, guide cannula was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were ICV injected with different doses of glutamate. In experiment 2, birds were administered with effective dose of glutamate after bicuculline. In experiment 3, chickens received muscimol prior to the injection of glutamate, and cumulative food intake was determined at 3-h postinjection. The results of this study showed that glutamate decreases food consumption in FD24 broiler cockerels (P ≤ 0.05), and this reduction occurs in a dose-dependent manner. Moreover, the inhibitory effect of glutamate on food intake was significantly increased with bicuculline pretreatment, and this effect was attenuated with muscimol (P ≤ 0.05). These results suggest that there is an interaction between glutamatergic and GABAergic systems (through GABA_A receptor) on food intake in broiler cockerels.