Insulin normalized brain metabolic status on a Model of Anorexia Nervosa in Mice.

INTRODUCTION: Anorexia nervosa is a psycho-socio-biological disease, characterized by self-starvation and distorted perception of body weight. Patients often over-exercise. Insulin is an anabolic hormone that increases food intake and restores body fat and is present in low levels in anorexia nervosa patients: thus may have therapeutic potential in treating anorexia nervosa. AIMS: to explore whether low levels insulin administration may result in recovery of cerebral function and restoration of metabolic disorder providing a treatment option for anorexia nervosa. METHODS: Female Sabra mice maintained on DR of 2.0 hours per day for 32 days, in cages with or without wheel attached to an electronic counter (activity wheel). They were then permitted to eat ad libitum for additional 15 days. On the second week, mice were injected ip with 0.5U/kg long acting Insulin(Lantus) or saline and cognitive function was evaluated. Insulin administered three times a week during days 8-32. Mice euthanized on day 48 and cerebral levels of monoamines, 2-AG and expression of genes associated with metabolic status were evaluated. RESULTS: Activity wheel mice decreased body weight, 2-AG, dopamine levels and 5-HT1A and increased Camkk2 and SIRT1 gene expression compared to mice without it. Insulin increased body weight, decreased revolutions, enhanced NPY and normalized Camkk2, SIRT-1, BDNF, elevated 2-AG and improved cognition in the wheel group. CONCLUSION: low dose insulin administration to animal model of anorexia associated with exercise, led to alterations and normalization in brain metabolic status and improved cognition. Insulin should be further explored as potential novel treatment for anorexia nervosa.

Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice.

OBJECTIVES: We have shown the beneficial effects of cannabinoids in a murine model of hepatic encephalopathy following thioacetamide and now report their effects on the liver injury. METHODS: Fulminant hepatic failure (FHF) was induced by administration of 200 mg/kg thioacetamide to wild-type (WT) and CB2 Knockout (KO) mice. Twenty-four hours later, mice were injected with 2-arachidonoylglycerol (CB1, CB2, and TRPV1 agonist), HU308 (CB2 agonist), SR141716 A (CB1 receptor blocker), SR141716 A+2-AG, and SR144528 (CB2 receptor blocker), capsaicin and capsazepine (TRPV1 agonist and antagonist receptors). Mice were sacrificed 2 days after thioacetamide administration (day 3) and liver biochemistry and histopathology as well as evaluation of 2-arachidonoylglycerol levels were performed on liver tissue. RESULTS: Liver histopathology undertaken 48 h after thioacetamide showed evidence of necrosis and inflammation. SR141716 A, HU308, and 2-arachidonoylglycerol reduced inflammation and promoted regeneration 1 day after their administration. Liver enzymes increased after thioacetamide administration and were reversed after SR141716 A and 2-arachidonoylglycerol administered alone or combined, HU-308, but not SR144528. Thus, the beneficial effects mediated through CB2 receptors. However, CB2 KO mice still modulated liver function via the TRPV1 receptors. Capsaicin improved both liver pathology and function in WT thioacetamide-treated mice, while capsazepine impaired it. CONCLUSIONS: The similar pattern found between the effect of cannabinoids and their antagonists on brain and liver indicated that the therapeutic effect might be directed by the improvement in both organs through CB2 receptors and/or TRPV1 receptors. Modulation of these systems may have therapeutic potential.

2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, in various rat tissues during the evolution of experimental cholestatic liver disease.

BACKGROUND/AIM: Changes in tissue levels of 2-arachidonoylglycerol (2-AG), an endocannabinoid, during the evolution of bile duct ligation (BDL) may indicate that endocannabinoids have a role in the hemodynamic changes that occur in this condition. METHODS: 2-AG levels, in various organs and vascular beds of BDL rats, 2 and 4 weeks post surgery, were determined. Untouched and sham-operated (SO) rats were used as controls. RESULTS: 2-AG content of a specific organ was not a static finding and depended on the rat's age, the time from the surgical procedure and the type of procedure. The most pronounced changes were observed in BDL rats 4 weeks post surgery. In these rats, hepatic, pulmonary, cardiac and renal medullary and papillary 2-AG levels were highest observed. No changes in splenic, aortic and renal cortical 2-AG levels were observed. In addition a stepwise increase in 2-AG levels from the cortex to the papilla was detected and was followed by a decrease in creatinine clearance. CONCLUSIONS: 2-AG probably has a role in the pathophysiologic changes in the liver, heart, lung and kidney that follows BDL.

The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells.

Diabetic neuropathy (DN) is a common complication of diabetes mellitus resulting in cognitive dysfunction and synaptic plasticity impairment. Hyperglycemia plays a critical role in the development and progression of DN, through a number of mechanisms including increased oxidative stress. Cannabinoids are a diverse family of compounds which can act as antioxidative agents and exhibit neuroprotective properties. We investigated the effect of the synthetic cannabinoid HU-210 on brain function of streptozotocin (STZ)-induced diabetic mice. These animals exhibit hyperglycemia, increased cerebral oxidative stress and impaired brain function. HU-210, through a receptor independent pathway, alleviates the oxidative damage and cognitive impairment without affecting glycemic control. To study the neuroprotective mechanism(s) involved, we cultured PC12 cells under hyperglycemic conditions. Hyperglycemia enhanced oxidative stress and cellular injuries were all counteracted by HU-210-in a dose dependent manner. These results suggest cannabinoids might have a therapeutic role in the management of the neurological complications of diabetes.

Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice.

Endocannabinoids function as neurotransmitters and neuromodulators in the central nervous system via specific receptors and apparently have a neuroprotective role. We assumed that the endocannabinoid system could be involved in the pathogenesis of hepatic encephalopathy (HE), a neuropsychiatric syndrome due to liver disease. We used a mouse model of a thioacetamide induced fulminant hepatic failure. We found that the levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) were elevated in the brain. Treatment with either 2-AG or with the CB1 receptor antagonist, SR141716A, improved a neurological score, activity and cognitive function. Activation of the CB2 receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB2 receptor antagonist SR144528A. The CB1 receptor agonist noladin ether was inactive. We conclude that the endocannabinoid system may play an important role in the pathogenesis of HE. Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential.

Very low doses of delta 8-THC increase food consumption and alter neurotransmitter levels following weight loss.

We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.

Short-term fasting and prolonged semistarvation have opposite effects on 2-AG levels in mouse brain.

2-Arachidonoyl glycerol (2-AG) levels in whole mouse brain and two of its regions-hippocampus and hypothalamus-were determined after diet restriction (between 60 and 40%) lasting 12 days. The diet restriction lowered the level of 2-AG, which in the hypothalamus depended on the severity of the diet restriction, while the level in the hippocampus was not dependent on the diet regimen. As these observations differ from previously published data showing elevation of 2-AG levels in rat brain after 24 h of severe food restriction, we measured 2-AG levels in whole mouse brain after a comparable period of full starvation (fasting). We confirmed the elevation of 2-AG levels. It seems possible that these time-dependent variations of 2-AG levels may be of importance as a general coping strategy by animals during periods of starvation.