Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

SPME as a green sample-preparation technique for the monitoring of phytocannabinoids and endocannabinoids in complex matrices

The endocannabinoid system(ECS),particularly its signaling pathways and ligands,has garnered considerable interest in recent years.Along with clinical work investigating the ECS’functions,including its role in the development of neurological and inflammatory conditions,much research has focused on developing analytical protocols enabling the precise monitoring of the levels and metabolism of the most potent ECS ligands:exogenous phytocannabinoids(PCs)and endogenous cannabinoids(endocannabinoids,ECs).Solid-phase microextraction(SPME)is an advanced,non-exhaustive sample-preparation technique that facilitates the precise and efficient isolation of trace amounts of analytes,thus making it appealing for the analysis of PCs and ECs in complex matrices of plant and animal/human origin.In this paper,we review recent forensic medicine and toxicological studies wherein SPME has been applied to monitor levels of PCs and ECs in complex matrices,determine their effects on organism physiology,and assess their role in the development of several diseases.

Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows

Background:Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system(ECS)by decreasing the availability of arachidonic acid,thus lowering endocannabinoids(e CBs)levels.The ECS is a modulator of energy metabolism,stress response and inflammation in mammals,yet there is little information on the roles of the ECS in transition dairy cows.During the periparturient period,the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation;however,exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows'physiology.Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows,by supplementing twenty-eight transition Holstein dairy cows with either saturated fat(CTL)or encapsulated flaxseed oil(FLX).Components of the ECS,metabolic and inflammatory markers were measured in blood,liver,and subcutaneous adipose tissue.Results:FLX supplementation reduced feed intake by 8.1%(P<0.01)and reduced plasma levels of arachidonic acid(by 44.2%;P=0.02)and anandamide(by 49.7%;P=0.03)postpartum compared to CTL.The m RNA transcription levels of the cannabinoid receptor 1(CNR1/CB1)tended to be lower(2.5 folds)in white blood cells of FLX than in CTL(P=0.10),and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL(P=0.04).In adipose tissue,palmitoylethanolamide levels were lower in FLX than in CTL(by 61.5%;P=0.02),relative m RNA transcription of lipogenic genes were higher,and the protein abundance of cannabinoid receptor 2(P=0.08)and monoacylglycerol lipase(P=0.10)tended to be higher in FLX compared to CTL.Hepatic 2-arachidonoylglycerol tended to be higher(by 73.1%;P=0.07),and interlukin-6 m RNA transcription level was 1.5 folds lower in liver of FLX than in CTL(P=0.03).Conclusions:Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation,which could be related to lower feed intake.The altered ECS components in blood,adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.

A proposed modulatory role of the endocannabinoid system on adipose tissue metabolism and appetite in periparturient dairy cows

To sustain the nutrient demands of rapid fetal growth,parturition,and milk synthesis,periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis.This process induces an inflammatory response within AT that is resolved as lactation progresses;however,excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases.The suppression of lipolytic action and inflammation,along with amplification of adipogenesis and lipogenesis,serve as prospective therapeutic targets for improving the health of periparturient dairy cows.Generally,the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis,suppresses lipolysis,and increases appetite in mammals.These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows’health,although much is still to be revealed in this context.This review summarizes the current knowledge surrounding the components of the endocannabinoid system,elaborates on the metabolic effects of its activation,and explores the potential to modulate its activity in periparturient dairy cows.

Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.

Homeostatic regulation of brain functions by endocannabinoid signaling

Humans have been using Cannabis and its extracts for a few thousand years as a medicinal and recreational drug. How- ever, the chemical component in Cannabis sativa, △9-tet- rahydrocannabinol （△9-THC）, an exogenous cannabinoid, remained unknown until it was isolated and identified as the main psychoactive ingredient （Gaoni and Mechoulam, 1964）.

Function of the Endocannabinoid System in Neurodegenerative Diseases and Cancers

Neurodegenerative diseases are characterized by progressive degeneration and/or death of neuronal cells and results in a wide array of cognitive impairments and other serious neurological defects. The signaling pathways and definite cause underlying the development of neurodegenerative nerve diseases have not been well defined. There is evidence of mechanisms within the endocannabinoid system that may suggest important pathways involved the progression of neurodegenerative diseases as well as some cancers. The endocannabinoid system is an endogenous ubiquitous neuromodulatory system that plays a critical in the development of the central nervous system (CNS), synaptic plasticity, as well as other primary neuronal functions. The recent identification of various cannabinoid receptors and their endogenous lipid ligands has generated an interest and significant increase in research of the endocannabinoid system and its role in human health and diseases. The Endocannabinoid system possesses essential endogenous receptors—cannabinoid receptors type 1 (CB1R) and type 2 (CB2R)—which are involved in mechanisms that contribute to the progression of neurodegenerative diseases and some cancers. In this review, we discuss the role of the endocannabinoid system in various neurodegenerative diseases as well as some cancers, and its promise as a targeted pharmacological therapy for patients of neurodegenerative diseases.

<i>Morinda citrifolia</i>(Noni) Fruit Juice Inhibits Endocannabinoid Degradation Enzymes

Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredient of the product studied in these clinical trials was juice made from noni fruit puree from French Polynesia, it was evaluated for its ability to inhibit the two major endocannabinoid degradation enzymes in vitro. Noni fruit juice inhibited both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a concentration-dependent manner, suggesting that it may help maintain anandamide and 2-arachidonoylglycerol levels. Samples of the puree were also analyzed for the presence of characteristic phytochemical markers of authentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic acid and asperulosidic acid, all of which were present. Also present was scandoside, which is reported for the first time as being identified in noni fruit or its juice. Some of these compounds may contribute to the FAAH and MAGL inhibiting activity of noni juice. These results reveal another set of mechanisms by which noni juice possibly supports mental health, maintains joint health, relieves discomfort and modulates the immune system.

The Endocannabinoid, 2-Arachidonoyl Glycerol, Induces Growth Cone Collapse and Neurite Retraction in Growing Peripheral Sensory Neurons

Cannabis has a detrimental impact on the developing nervous system. Therefore, regular consumption of cannabis by pregnant and lactating woman poses a potential risk to neuronal growth in fetuses and infants. Indeed, endogenous cannabis-like molecules called endocannabinoids regulate many physiological processes, including neurogenesis, axon guidance, and synaptic plasticity through CB1 receptors. To investigate the physiological role of CB1 receptors on peripheral sensory nerve growth, the endocannabinoid 2-arachidonoyl glycerol was added to cultured chick dorsal root ganglion neurons. This compound inhibited neurite elongation and induced growth cone collapse in a dose- and time-dependent manner. These data suggest that caution should be exercised regarding maternal cannabis use during pregnancy. Because ectopic sprouting and abnormal neuronal network connections are considered to be a cause of neuropathic pain, our current data imply an additional role of endocannabinoids as inhibitors of the formation of pain-maintenance networks.

Drinking during pregnancy: Potential role of endocannabinoid signaling in fetal alcohol effects

Alcohol is a well-recognized teratogen that can causevariable physical and behavioral effects on the fetus.Alcohol use and abuse during pregnancy is one of the major health and societal problems and has been linked to a wide range of birth defects in the offspring collectively termed as fetal alcohol spectrum disorder(FASD). The severity of abnormalities may depend on a number of factors that include the amount, the frequency, the period during gestation and the route of alcohol administration. The current knowledge about the neurobiological basis of FASD is limited. However, recent studies have suggested that the membrane-derived lipids especially bioactive endogenous cannabinoids(eCB)such as arachidonyl ethanolamide and 2-arachidonyl glycerol resulting from alcohol exposure, may play a significant role in modulating neurophysiological and neurobehavioral effects in chronic alcohol exposed adult animals. Based on these findings and on reported studies on the role of eCB signaling in neurodevelopment and behavior, it is speculated that the eC B signaling may play a critical role in fetal alcohol syndrome and FASD-related behavioral effects. The current discussion will touch upon some of the mechanistic explanations about the role of eCB signaling system in FASD and provide further guidance for future direction.

The Endocannabinoid,Anandamide,Induces Cannabinoid Receptor-Independent Cell Death in Renal Proximal Tubule Cells

Background: The endocannabinoid (EC) system is well characterized in the central nervous system but scarcely studied in peripheral organs. In this paper, we newly identify the effect of the EC anandamide (AEA) upon renal proximal tubule cells. Methods: Measurement of lactate dehydrogenase (LDH) release after treatment of primary renal proximal tubule cells (RPTEC) and renal carcinoma cell line (Caki-1) with AEA, arachidonic acid (AA), ethanolamide (EtAm), EC receptor CB1 antagonist (AM251), CB2 receptor antagonist (SR144528), TRPV1 receptor antagonist (capsazepine), degradation enzyme fatty acid amide hydrolase (FAAH) antagonist (URB597), antioxidants GSH-EE;Trolox, GSH depletor BSO, membrane cholesterol depletor (MCD), apoptosis inhibitor zVAD, necroptosis inhibitor Nec-1 or ferroptosis inhibitor Fer-1. Western blot and qRT-PCR analysis plus determination of reactive oxygen species (ROS) via H2-DCFDA were performed. Histology for EC enzymes, N-acetylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and FAAH, as well as the determination of physiological levels of ECs in human and rat renal tissue via liquid chromatography were conducted. Results: AEA both dose- and time-dependently induces cell death in RPTEC and Caki-1 within hours, characterized by cell blebbing, not influenced by blocking the described EC receptors by AM251, SR144528, capsazepine or FAAH by URB597 or MCD. Cell death is mediated via ROS. There is no difference found in the histology of the enzymes FAAH and NAPE-PLD in human renal tissue with interstitial nephritis. Blocking of apoptotic, necroptotic or ferroptotic cell death does not lead to a reduction in LDH release in vitro. Conclusion: The endocannabinoid anandamide induces cell death in renal proximal tubule cell in a time- and dose-dependent manner. This pathway is mediated via ROS and is independent of cannabinoid receptors, membrane cholesterol or FAAH activity.

Endocannabinoid system: A newer molecular target for the treatment of alcohol-related behaviors

The cannabinoid(CB) receptors, endocannabinoids(e CB) and their synthesizing and catabolizing enzymes and the proteins involved in their transport, constitute what is now recognized as the e CB system. The e CBs are a class of lipids that have been identified as retrograde messengers and produce their effects via presynaptic CB receptors. The major function of the e CBs has been suggested to be that of modulating the release of several neurotransmitters implicated in a number of biological functions that include reward and reinforcement. There is now significant evidence to suggest that the e CB system plays an important role in the development of alcohol tolerance, dependence and re-lapse. Recent studies suggest that the pharmacological manipulation of the e CB system has the potential not only to block the direct reinforcing properties of alcohol but also alleviate behavioral abnormalities associated with relapse. There is also accumulating evidence that points to the possible utility of the e CB system targeted drugs in the treatment of alcoholismrelated behavioral disorders. The agents that block CB1 receptor function or inhibit the synthesis of e CBs are attractive candidate drugs that need to be explored. Further understanding of the role of the e CB system in molecular mechanism/s that underlies alcoholism-related behaviors should lead to a better treatment of this devastating disorder.

Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation

Globally,it is evident that glioblastoma multiforme(GBM)is an aggressive malignant cancer with a high mortality rate and no effective treatment options.Glioblastoma is classified as the stage-four progression of a glioma tumor,and its diagnosis results in a shortened life expectancy.Treatment options for GBM include chemotherapy,immunotherapy,surgical intervention,and conventional pharmacotherapy;however,at best,they extend the patient’s life by a maximum of 5 years.GBMs are considered incurable due to their high recurrence rate,despite various aggressive therapeutic approaches which can have many serious adverse effects.Ceramides,classified as endocannabinoids,offer a promising novel therapeutic approach for GBM.Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells.Cannabinoids promote atypical protein kinase C,deactivate fatty acid amide hydrolase enzymes,and activate transient receptor potential vanilloid 1(TRPV1)and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids.In previous in vivo studies,endocannabinoids,chemically classified as amide formations of oleic and palmitic acids,have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis,which have potential as a novel therapy for GBM.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

△^(9)-四氢大麻酚对血脑屏障作用的研究进展

大麻素的精神活性是众所周知的,关于大麻素在全世界是否可以用于治疗也一直存在争议。而Δ^(9)-四氢大麻酚(Δ^(9)-tetrahydrocannabinol,THC)作为大麻中最主要的精神活性物质,它的神经作用机制直到最近才被发现,但其作用机理仍未完全明确。血脑屏障(blood-brain barrier,BBB)是保护大脑的关键屏障结构,也是外来物质入脑的第一道防线,THC的亲脂性及与内源性大麻素系统的相互作用使其更加容易对BBB产生作用。本文综述了THC的神经毒理作用,聚焦于THC对BBB的作用与机制,为阐明THC的神经作用机制提供理论依据。

情绪护肤的生理学基础综述

对情绪与皮肤相互影响的生理通路进行了总结梳理,将生理通路分为心理应激、昼夜节律、大麻素系统和各类感觉受体进行讨论,并列举了相关的护肤原料和功效检测维度。综述了情绪护肤领域的科学进展和发展趋势,对未来的研究方向提出一些建议。

The endocannabinoid system： ＇NO＇ longer anonymous in the control of nitrergic signalling？

endocannabinoid 系统(ECS ) 是在多样的细胞的功能的规定被含有的一个关键细胞的发信号系统。重要地，种证据建议部分地， ECS 的生物行动可以通过它调整氮的氧化物的生产或版本的能力被调停，一个无所不在的 bioactive 分子，哪个是的功能万用的发信号中介。此处，我们考察并且讨论在由加亮支持 ECS 功能的 nitrergic 调整的新兴的工作调整导致 ECS 的信号 transduction 与反应的氮种类的氮的氧化物生产，以及参与的调停 ECS 的规定相关的证据。重要地，构画出的研究表明在表明系统的 ECS 和 nitrergic 之间的相互作用能是 stimulatory 并且在自然禁止，取决于细胞的上下文。而且，如此的串音可以行动维持合适的房间功能，而在任何一个系统的畸形能破坏细胞的 homoeostasis 并且贡献与他们的 dysregulation 联系的各种各样的病理。因而，指向这些发信号的系统的未来研究可以提供新卓见进在疾病开发表明轴的 ECS 氮的氧化物的潜在的角色或为 nitrosative 的处理导致新奇治疗学的目标的鉴定压力相关的神经病学、心血管、新陈代谢的混乱。

Effects of Chaiyuwendan decoction on endocannabinoids levels in adipose tissue of rats with chronic stress-induced depression

OBJECTIVE:To investigate how Chaiyuwendan decoction(CWD)affects endocannabinoid levels in the adipose tissue of depressed rats.METHODS:Twenty-four male Sprague-Dawley rats were randomly divided into four groups with six rats in each.One group was randomly selected as the control group.The remaining three groups were subjected to chronic stress to induce depression.Groups were randomly assigned as a model group,CWD group,and amitriptyline group.CWD was given to the CWD group once a day from the second day of modeling.The amitriptyline group was administered amitriptyline intragastrically(10 mg/kg)once a day.After treatment for 21 days,body weight and fat weight were measured and the levels of N-arachidonoylethanolamine(AEA),2-arachidonoylglycerol(2-AG),and N-palmitoylethanolamine(PEA)in adipose tissue were determined with liquid chromatography-mass spectrometry.RESULTS:Compared with the control group,body weight,fat weight,AEA,and PEA were significantly lower,and 2-AG was higher,in the model group(P<0.05,P<0.01).Compared with the model group,body weight,fat weight,the AEA,and PEA levels were significantly higher,and 2-AG level was significantly lower in the CWD group(P<0.05).However,the levels did not differ significantly between the CWD group and the amitriptyline group.CONCLUSION:CWD could regulate the levels of AEA,2-AG,and PEA in rats with depression induced by chronic stress.

间质性膀胱炎/膀胱疼痛综合征诊治进展

间质性膀胱炎/膀胱疼痛综合征(IC/BPS)是表现为与膀胱相关的疼痛、压迫感或不适且伴有下尿路症状,症状持续6周(或6个月)以上的一组症候群。自首次报道至今,该病始终是临床诊治的难题,也一直经历着认知革新,其涉及疾病分类分型、相关基础研究、影像学、症状评分、膀胱镜检、治疗以及新的潜在治疗靶点内源性大麻素系统等诸多方面,亦是本文要点。

Medicinal cannabis products for the treatment of acute pain

For thousands of years,medicinal cannabis has been used for pain treatment,but its use for pain management is still controversial.Meta-analysis of the literature has shown contrasting results on the addition of cannabinoids to opioids compared with placebo/other active agents to reduce pain.Clinical studies are mainly focused on medicinal cannabis use in chronic pain management,for which the analgesic effect has been proven in many studies.This review focuses on the potential use of medical cannabis for acute pain management in preclinical studies,studies on healthy subjects and the few pioneering studies in the clinical setting.