Endocannabinoid system in food intake and metabolic regulation

PURPOSE OF REVIEW: As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology. RECENT FINDINGS: The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood. SUMMARY: The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes.     

Efficacy of DL-α lipoic acid against systemic inflammation-induced mice: antioxidant defense system

Inflammation can activate macrophages or monocytes and sequentially release several inflammatory cytokines and reactive oxygen species (ROS). Oxidative stress-induced acute inflammatory response plays an important role in several diseases. This study was designed to investigate the prophylactic effect of the antioxidant lipoic acid (LA) during inflammation-induced mice. Mice were divided in to three groups (n = 8 in each): control, systemic inflammation, and LA treated mice with systemic inflammation. Results show that ROS was significantly higher in lymphocytes, hepatocytes, and astrocytes (P < 0.05) of inflammation induced mice when compared with control but no significant changes were observed in the LA treated group. Increased levels of lipid peroxidation (LPO) and decreased activities of oxidants such as superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione, and ATPase were observed in the inflammation-induced mice, which returned to near normalcy following LA therapy. In vitro study has shown that LA treatment not only suppresses the increased LPO levels but also inhibits the lipid break down resulting from autoxidation. In addition, increased immunoreactivity of the astrocyte marker glial fibrillary acidic protein (GFAP) was observed in the neocortex region of inflammation-induced mice, whereas nuclear factor kappa B p65 (NFkappaB) immunoreactivity was observed in both the neocortex and liver of the same group which were effectively controlled by LA therapy suggesting that LA can efficiently manage systemic inflammation.     

The neuroprotective role of melatonin against amyloid beta peptide injected mice

Widespread cerebral deposition of a 40-42 amino acid peptide called amyloid beta peptide (A beta) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease (AD). The clinical study provides evidence that accumulation of protofibrils due to the Arctic mutation (E22G) causes early AD onset. Melatonin showed beneficial effects in an AD mouse model. Mice were divided into four different groups (n=8 per group): (i) control group, (ii) scrambled A beta-injected group, (iii) A beta protofibril-injected group and (iv) melatonin-treated group. A single dose of (5 microg) A beta protofibril was administered to the A beta protofibril-injected and melatonin-treated groups via intracerebroventricular injections. The results demonstrate that melatonin treatment significantly reduces A beta protofibril-induced reactive oxygen species (ROS) production, intracellular calcium levels and acetylcholinesterase activity in the neocortex and hippocampus regions. Based on these findings it is suggested that melatonin therapy might be a useful treatment for AD patients.     

Role of fibrillar Abeta25-35 in the inflammation induced rat model with respect to oxidative vulnerability

The major pathological ramification of Alzheimer's disease (AD) is accumulation of beta-Amyloid (Abeta) peptides in the brain. An emerging therapeutic approach for AD is elimination of excessive Ass peptides and preventing its re-accumulation. Immunization is the most effective strategy in removing preexisting cerebral Abetas and improving the cognitive capacity as shown in transgenic mice model of AD. However, active immunization is associated with adverse effect such as encephalitis with perivascular inflammation and hemorrhage. Details about the mechanistic aspects of propagation of these toxic effects are matter of intense enquiry as this knowledge is essential for the understanding of the AD pathophysiology. The present work aimed to study the oxidative vulnerability in the plasma, liver and brain of the inflammation-induced rats subjected to Ass immunization. Induction of inflammation was performed by subcutaneous injection of 0.5?ml of 2% silver nitrate. Our present result shows that the proinflammatory cytokines such as IL1alpha and TNFalpha are increased significantly in the inflammation-induced, Abeta1-42, Abeta25-35 treated groups and inflammation with Abeta25-35 treated group when compared to control, complete Freund's adjuvant and Abeta35-25 treated groups. These increased proinflammatory cytokines concurrently releases significant amount of free radicals in the astrocytes of respected groups. The present result shows that nitric oxide (NO) level was significantly higher (P<0.001) in plasma, liver and brain of the rat subjected to inflammation, Abeta1-42, Abeta25-35 and inflammation with Abeta25-35 injected groups when compared to control. The increased level of lipid peroxides (LPO) (P<0.001) and decreased antioxidant status (P<0.05) were observed in the plasma, liver and brain of inflammation-induced group when compared to control. Our result shows that significant oxidative vulnerability was observed in the inflammation with Ass treated rats when compared to other groups. Based on our results, we suggest that immunization of AD patients with Ass should be done with caution as the increase in Ass could trigger the brain inflammation in uncontrollable level.     

The protective role of DL-α-lipoic acid in the oxidative vulnerability triggered by Aβ-amyloid vaccination in mice

Recent reports indicate that -amyloid peptide (A) vaccine based therapy for Alzheimers disease (AD) may be on the horizon. There are however, concerns about the safety of this approach. Immunization with A has several disadvantages, because it crosses the blood brain barrier and cause inflammation and neurotoxicity. The present work is aimed to study the protective effective of -lipoic acid (LA) in the oxidative vulnerability of -amyloid in plasma, liver, spleen and brain, when A fibrils are given intraperitoneally in inflammation induced mice. Result shows that reactive oxygen species (ROS) in the astrocytes of inflammation induced mice along with A (IA) has shown 2.5-fold increase when compared with LA treated mice. The increased level of lipid peroxidase (LPO) (p < 0.05) and decreased antioxidant status (p < 0.05) were observed in the plasma, liver, spleen and brain of IA induced mice when compared with LA treated mice.Data shows that there were no significant changes observed between the control and LA treated mice. Our biochemical and histological results highlight that significant oxidative vulnerability was observed in IA treated mice, which was prevented by LA therapy. Our findings suggest that the antioxidant effect of LA when induced with A may serve as a potent therapeutic tool for inflammatory AD models. (Mol Cell Biochem 270: 29–37, 2005)     

Heparan sulfate in lung morphogenesis: The elephant in the room

Heparan sulfate (HS) is a structurally complex polysaccharide located on the cell surface and in the extracellular matrix, where it participates in numerous biological processes through interactions with a vast number of regulatory proteins such as growth factors and morphogens. HS is crucial for lung development; disruption of HS synthesis in flies and mice results in a major aberration of airway branching, and in mice, it results in neonatal death as a consequence of malformed lungs and respiratory distress. Epithelial–mesenchymal interactions governing lung morphogenesis are directed by various diffusible proteins, many of which bind to, and are regulated by HS, including fibroblast growth factors, sonic hedgehog, and bone morphogenetic proteins. The majority of research into the molecular mechanisms underlying defective lung morphogenesis and pulmonary pathologies, such as bronchopulmonary dysplasia and pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), has focused on abnormal protein expression. The potential contribution of HS to abnormalities of lung development has yet to be explored to any significant extent, which is somewhat surprising given the abnormal lung phenotype exhibited by mutant mice synthesizing abnormal HS. This review summarizes our current understanding of the role of HS and HS‐binding proteins in lung morphogenesis and will present in vitro and in vivo evidence for the fundamental importance of HS in airway development. Finally, we will discuss the future possibility of HS‐based therapeutics for ameliorating insufficient lung growth associated with lung diseases such as CDH. Birth Defects Research (Part C) 90:32–44, 2010. © 2010 Wiley‐Liss, Inc.