内源性大麻素样系统与肥胖

内源性大麻素样系统主要由内源性大麻素及其受体组成,后者分为CB1受体和CB2受体两种,激活后可引起摄食增加。与正常小鼠相比,CB1受体(-/-)小鼠的体重和脂肪明显减少,即使在致肥胖饮食条件下也不会发生肥胖或胰岛素抵抗。研究证实,CB1受体拮抗剂可通过中枢和外周两种机制抑制摄食并改善代谢;其中,利莫那班已进入Ⅲ期临床试验,可有效抑制食欲、减轻体重,并且尚未发现明显的副作用。     

内源性大麻素系统对肝硬化的影响

内源性大麻素系统包括内源性大麻素物质、特异性大麻素受体1(cannabinoid receptor1,CB1)和大麻素受体2(cannabinoid receptor2,CB2).许多研究已经证实在慢性肝病发展过程中,肝脏肌成纤维细胞和血管内皮细胞的CB1和CB2表达升高,内源性大麻素系统与肝纤维化及肝硬化关系密切.本文就内源性大麻素系统、内源性大麻素系统和脂肪性肝病、内源性大麻素系统和肝纤维化、内源性大麻素系统和肝硬化并发症等作一综述.     

氧化型低密度脂蛋白诱导巨噬细胞内源性大麻素系统激活

目的 探讨氧化型低密度脂蛋白刺激能否诱导巨噬细胞内源性大麻素系统激活.方法 体外常规培养RAW264.7小鼠巨噬细胞,加入氧化型低密度脂蛋白或溶媒孵育24 h,用高效液相色谱分析技术检测巨噬细胞内源性大麻素Anandamide和2-arachidonoylglycerol水平,以实时定量PCR技术和免疫印迹法对大麻素CB1、CB2受体和血小板活化因子受体mRNA和蛋白的表达进行分析.结果 内源性大麻素2-arachidonoylglycerol水平在6mg/L和12 mg/L氧化型低密度脂蛋白刺激时分别升高了2.4倍和4.8倍,而Anandamide水平无明显变化.3～12mg/L氧化型低密度脂蛋白刺激时,RAW264.7巨噬细胞大麻素CB1和CB2受体及血小板活化因子受体mRNA和蛋白的表达均明显上调(P＜0.01).结论 首次证实氧化型低密度脂蛋白通过激活血小板活化因子受体诱导巨噬细胞内源性大麻素系统激活,提示氧化型低密度脂蛋白致动脉粥样硬化过程中可能涉及该系统的激活.     

大麻素受体2与几种消化系统疾病

内源性大麻素系统包括内源性大麻素物质、特异性大麻素受体1(cannabinoid receptor 1,CB1)和CB2.内源性大麻素系统在胃肠道疾病、肝脏疾病、胰腺疾病和肿瘤的发生发展过程中扮演了众多的生理效应和病理生理角色.本文就内源性大麻素系统、CB2与肠易激综合征、炎症性肠病、胰腺炎、肝脏疾病及消化系肿瘤的关系等作一综述.     

内源性大麻素调节去甲肾上腺素对肝星状细胞作用的研究

交感神经释放的神经递质对肝纤维化发展和促进肝纤维化时的损伤修复都有很重要的调节作用[1].有研究表明,内源性大麻素(anandamide,AZA)作为中枢神经系统中的神经调节因子,与其大麻素CB1、CB2受体对大脑中神经递质的释放起着重要的调节作用,但其对肝脏中神经递质释放的调节及协同神经递质对肝星状细胞(HSC)增殖、活化的调控国内外报道甚少.     

内源性大麻系统与代谢综合征

大麻是一种成瘾性药物,其使用受到严格的限制,然而大麻类物质还具有止痛、镇静、降低血压、抗痉挛等多种药理作用。1964年,Gaoni和Mechoulam确定并纯化了大麻的主要活性成分△9四氢大麻醇（A9THC）,之后Devane等。发现脑内存在一种大麻受体。1993年,研究从脾脏及巨噬细胞等免疫器官（组织）中发现了另一种大麻受体,由此将在脑内发现的大麻受体称为CB1受体,而将外周的大麻受体称为CB2受体,两的同源性为44％。继而研究发现CB1受体除了在脑组织中有丰富的表达外,在脂肪组织、肾上腺、心脏、血管等许多外周器官中也有表达;CB2受体则在免疫组织中表达量最多,在许多其他外周组织中有较低表达。1992年,研究分离出首个内源性大麻样物质花生四烯酸乙醇胺（anandamide）,因其与其后发现的若干物质能与内源性大麻受体结合而命名为“内源性大麻样物质”。     

大麻素受体1通过多种机制促进肝细胞癌的发生和进展

<正>【据《Hepatology》2015年5月报道】题:大麻素受体1通过多种机制促进肝细胞癌的发生和进展(作者Mukhopadhyay B等)肝细胞癌(HCC)的死亡率高且治疗方法有限。内源性大麻素与肝大麻素1受体相互作用(CB1Rs)诱导参与有丝分裂的细胞周期蛋白,包括叉头框M1,可促进再生的肝细胞增殖。由于该蛋白在肝癌组织中高表达,有助于其发生、发展过程,来自美国国立卫生研究院的Mukhopadhyay B等分析了小鼠及人类肝癌中内源性大麻素系统/CB1R。出生后二乙基亚硝胺诱导野生型小鼠8个月建立肝癌模型。观察连续磁共振成像,在CB1R(-/)小鼠或外周拮抗剂处理的野生型小鼠体内发现较少和较小的肿瘤全基因组转录组分析显     

血管紧张素Ⅱ受体阻滞剂与神经保护

血管紧张素Ⅱ受体阻滞剂(ARB)通过阻滞1型血管紧张素Ⅱ受体(AT1受体)降低血压、逆转血管重构,激活2型血管紧张素Ⅱ受体(AT2受体)以提高血管紧张素Ⅱ(AngⅡ)水平扩张血管、抗增殖及调脂.进一步了解ARB在神经保护中的作用机制,可为临床治疗缺血性卒中提供新的思路.     

内源性大麻素系统与阻塞性睡眠呼吸暂停合并症

阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)是以睡眠过程中反复的上气道狭窄甚至完全闭塞导致频繁发生呼吸暂停为特征的睡眠呼吸障碍性疾病,该疾病与白天嗜睡、肥胖、高血压、缺血性心脏病、心律失常等均有明显的相关性.内源性大麻素系统(endocannabinoid system,ECS)是新近发现的信号系统,由内源性大麻素(endogenous cannabinoids,EC),大麻素受体CB1、CB2及合成、降解EC的酶类共同组成.在体内,ECS有广泛的生理学作用.     

血管紧张素Ⅱ2型受体心血管效应的研究进展

血管紧张素Ⅱ2型受体(angiotensin Ⅱ type 2 receptor,AT2受体)是近年的研究热点,其主要发挥拮抗血管紧张素Ⅱ1型受体(AT1受体)的作用,如调控血压、抑制心肌肥厚及纤维化、抑制血管重建、保护心功能等心血管效应。但尚存在一些研究不支持以上结论,这可能与AT2受体数量及功能在不同个体、组织类型、病理生理状态下存在差别有关。     

Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.     

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors

Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.     

Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength

The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.     

Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.

BACKGROUND & AIMS: Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis. METHODS: Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry. RESULTS: CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals. CONCLUSIONS: Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.     

Cardiovascular risk management by blocking the endocannabinoid system.

The specific blockade of endocannabinoids at the level of the cannabinoid receptor 1 (CB (1) receptor) is a new therapeutic option to reduce body weight and manage cardiovascular risk. Although clinical trials are underway to document the safety and efficacy of this approach, much is still unknown about this endogenous system. Endocannabinoids and their receptors are expressed in the central nervous system as well as in the periphery and regulate the central neural circuits for food uptake and peripheral metabolic circuits. Within the context of food uptake, the stimulation of the CB (1) receptor with Delta (9)-tetrahydrocannabinol (Delta (9)-THC) enhances food consumption, while its blockade with receptor antagonists is an emerging relevant therapeutic means to reduce body weight. Rimonabant is the first of a new class of drugs that interferes with the endocannabinoid system by blocking the CB (1) receptor. In recent clinical studies, a substantial reduction in body weight and waist circumference was associated with an improvement of the cardiovascular risk profile. In particular, increased HDL cholesterol, decreased serum triglycerides and improved insulin sensitivity were observed. Further research will serve to establish the role of these compounds in cardiovascular risk management.     

Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function

Cannabinoids and endocannabinoids negatively influence sperm functions. These substances have been demonstrated in many mammalian tissues, including male and female reproductive tracts, and previous studies have shown the presence of functional receptors for cannabinoids in human sperm. The present study, by means of RT-PCR and Western blot techniques, demonstrates that human sperm express the CB(1), but not CB(2), cannabinoid receptor (CB-R) subtype located in the head and middle piece of the sperm. The activation of this receptor by anandamide reduces sperm motility and inhibits capacitation-induced acrosome reaction. Activation of the CB(1)-R did not induce any variation in sperm intracellular calcium concentrations, but produced a rapid plasma membrane hyperpolarization that was reduced by the K(+) channel blocker tetraethylammonium. The effects of anandamide on human sperm motility were dependent on the reduction of sperm mitochondrial activity as determined by rhodamine 123 fluorescence. The specificity of anandamide effects in human sperm were confirmed by the effects of the CB(1)-R antagonist SR141716. These findings provide additional evidence that human sperm express functional CB(1)-R, the activation of which negatively influences important sperm functions, and suggest a possible role for the cannabinoid system in the pathogenesis of some forms of male infertility.     

Beta-caryophyllene is a dietary cannabinoid

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.     

HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor

Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)-transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.     

Impact of endocannabinoid system in modulation of cardiometabolic risk factors

Endocannabinoid system, the complex of specific cannabinoid receptors (CB1 and CB2 subtypes) and their endogenous agonistic ligands (endocannabinoids) plays, besides others, an important role in the central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism. Alterations of these functions are associated with endocannabinoid system hyperactivity. The cannabinoid receptor CB1 antagonist rimonabant normalizes the over activated endocannabinoid system which contributes to the regulation of energy homeostasis, and improves lipid and glucose metabolism--decreases body weight, waist circumference, intra-abdominal obesity and triglycerides, increases HDL-C, improves insulin sensitivity according to HOMA index. Results of the international multicentric clinical trials confirm that rimonabant is well tolerated and show antiatherogenic effects (increased adiponectin, decreased marker of inflammation CRP and improvement of LDL profile) as well as decreased percentage of subjects with NCEP/ATPIII (National Cholesterol Education Program Adult Treatment Panel III) defined metabolic syndrome. Thus, the CB1 cannabinoid receptor antagonist rimonabant is suggested to be a prospective drug decreasing cardiometabolic risk factors.