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Endocannabinoids and Liver Disease. I. Endocannabinoids and their receptors in the liver

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  “The medicinal properties of cannabis (Cannabis sativa, marijuana) have been known for millennia, as shown by reports from China and India underscoring its analgesic, antiemetic, and appetite-stimulating properties. During the 19th century, the prescription of cannabis gained popularity for a variety of conditions ranging from epilepsy to rheumatism and abdominal symptoms. Concerns about abuse led to discontinuation of therapeutic use in the 1940s. The characterization of marijuana-derived bioactive molecules began during the early 20th century with the identification of several hydrophobic compounds and culminated in 1964 with the isolation of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of the plant. Subsequent studies identified over 60 other phytocannabinoids and allowed the synthesis of active analogs with varying potencies. This step was critical in the identification of the endocannabinoid system, comprising specific cannabinoid binding sites (CB1 and CB2), their endogenous ligands (endocannabinoids), and synthetic and degradative pathways.”

“Cannabinoid receptors (CB1 and CB2) and their endogenous ligands (endocannabinoids) have recently emerged as novel mediators of liver diseases. Endogenous activation of CB1 receptors promotes nonalcoholic fatty liver disease (NAFLD) and progression of liver fibrosis associated with chronic liver injury; in addition, CB1 receptors contribute to the pathogenesis of portal hypertension and cirrhotic cardiomyopathy. CB2 receptor-dependent effects are also increasingly characterized, including antifibrogenic effects and regulation of liver inflammation during ischemia-reperfusion and NAFLD. It is likely that the next few years will allow us to delineate whether molecules targeting CB1 and CB2 receptors are useful therapeutic agents for the treatment of chronic liver diseases.”

http://ajpgi.physiology.org/content/294/1/G9.long

Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: Effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment.

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Abstract

“Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and cold allodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30mg/kg), gabapentin (100mg/kg), morphine (6mg/kg), URB597 (0.1 or 1mg/kg), URB937 (0.1 or 1mg/kg) or JZL184 (1, 3 or 8mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB(1) (AM251 3mg/kg), CB(2) (AM630 3mg/kg), TRPV1 (AMG9810 3mg/kg) or TRPA1 (HC030031 8mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB(1), CB(2), TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the neuropathy while amitriptyline, administered acutely, was ineffective. CB(1) or CB(2) antagonist completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation, while TRPV1 antagonist AMG9810 blocked only the anti-allodynic efficacy of both FAAH inhibitors, but not the MGL inhibitor. By contrast, the TRPA1 antagonist HC30031 did not attenuate anti-allodynic efficacy of any endocannabinoid modulator. When the levels of endocannabinoids were examined, cisplatin increased both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels in the lumbar spinal cord and decreased 2-AG levels (but not AEA) in dorsal hind paw skin. RT-PCR showed that mRNA for FAAH, but not other markers, was upregulated by cisplatin treatment in dorsal root ganglia. The present studies demonstrate that cisplatin alters endocannabinoid tone and that inhibition of endocannabinoid hydrolysis alleviates chemotherapy-induced mechanical and cold allodynia. The anti-allodynic effects of FAAH and MGL inhibitors are mediated by CB(1) and CB(2) cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms contribute to the anti-allodynic efficacy of FAAH (but not MGL) inhibitors. Strikingly, endocannabinoid modulators potently suppressed cisplatin-evoked allodynia with a rapid onset and showed efficacy that equaled or exceeded that of major classes of anti-neuropathic pain medications used clinically. Thus, inhibition of endocannabinoid hydrolysis, via FAAH or MGL inhibitors, represents an efficacious pharmacological approach for suppressing chemotherapy-induced neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/23127915

 

Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms

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 “Monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) degrade the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), respectively… peripheral inhibition of enzymes hydrolyzing 2-AG and AEA suppresses capsaicin-evoked behavioral sensitization with distinct patterns of pharmacological specificity… Modulation of endocannabinoids in the periphery suppressed capsaicin-evoked nocifensive behavior and thermal hyperalgesia through either CB1 or CB2 receptor mechanisms but suppressed capsaicin-evoked mechanical allodynia through CB1 mechanisms only. Inhibition of endocannabinoid transport was more effective in suppressing capsaicin-induced sensitization compared to inhibition of either FAAH or MGL alone. These studies are the first to unveil the effects of pharmacologically increasing peripheral endocannabinoid levels on capsaicin-induced behavioral hypersensitivities. Our data suggest that 2-AG, the putative product of MGL inhibition, and AEA, the putative product of FAAH inhibition, differentially suppress capsaicin-induced nociception through peripheral cannabinoid mechanisms.”

“Cannabis has been used for centuries for its pain-relieving properties. The main active ingredient of cannabis, Δ9-tetrahydrocannabinol, produces antinociception by binding to G protein-coupled CB1 and CB2 receptors. Cannabinoids produce antinociception in animal models of both acute and chronic pain.”

Read more: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900457/

FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels.

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Abstract

 “Apart from their widespread recreational abuse, the psychoactive preparations of the plant Cannabis sativa and its major psychotropic component, Delta9-tetrahydrocannabinol (THC), are also known for their medicinal properties. Following the identification of receptors for THC – the cannabinoid CB1 and CB2 receptors – in mammals, various pharmaceutical strategies have attempted to exploit the properties of the cannabinoid system while minimizing psychotropic side effects. The cloning of the cannabinoid CB1 and CB2 receptors enabled the discovery of the endogenous agonists of the receptors, the endocannabinoids, and eventually led to the identification of enzymes that catalyze endocannabinoid inactivation. Unlike exogenously administered THC and synthetic CB1 and CB2 agonists, the endocannabinoids that are produced endogenously following the onset of several pathologies may act in a site- and time-specific manner to minimize the consequences of such conditions. This observation has suggested the possibility of targeting endocannabinoid-degrading enzymes to prolong the precisely regulated pro-homeostatic action of endocannabinoids. Two major enzymes have been cloned and investigated thoroughly: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Inhibitors of these enzymes have demonstrated therapeutic benefit in animal models of several disorders, including neuropathic pain, anxiety and inflammatory bowel diseases, as well as against the proliferation and migration of cancer cells. This review describes the major biochemical properties of FAAH and MAGL, and the design and pharmacological properties of inhibitors of these enzymes.”

http://www.ncbi.nlm.nih.gov/pubmed/20047159

Therapeutic Potential of Monoacylglycerol Lipase Inhibitors.

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Abstract

 “Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown benefitial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/23142242

Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System

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“Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.”

“In summary, we provide data showing that MAGL is a critical modulator of 2-AG levels and functions and that the endocannabinoid system adapts to long-term elevation of 2-AG levels by down-regulating CB1 receptor density and signaling. Moreover, our gain of function in vivo model of 2-AG signaling sheds light on the physiological and pathophysiological consequences of long-term inhibition of MAGL, a pharmacological target with therapeutic potential for neurologic and metabolic diseases.”

http://molpharm.aspetjournals.org/content/78/6/996.long

Fatty acid amide hydrolase: a potential target for next generation therapeutics.

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Abstract

“Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipid mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutic drugs of potential value for the treatment of pathologies in the central nervous system and in the periphery. Here, the potential applications of these inhibitors for human disease will be reviewed, with an emphasis on the properties of hydro(pero)xy-anandamides. In fact, these oxygenated derivatives of AEA are the most powerful inhibitors of FAAH of natural origin as yet discovered. In addition, new insights into the promoter region of FAAH gene will be presented, and the therapeutic potential of mimetics of transcription factors of this gene in the management of human infertility will be discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/16472164

Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system.

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Abstract

“The family of endocannabinoids contains several polyunsaturated fatty acid amides such as anandamide (AEA), but also esters such as 2-arachidonoylglycerol (2-AG). These compounds are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta9-tetrahydrocannabinol (Delta9-THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake, through a putative membrane transporter, followed by intracellular degradation by fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutics of potential value for the treatment of pathologies of the central nervous system, and of peripheral tissues. Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors, are the topic of this chapter.”

http://www.ncbi.nlm.nih.gov/pubmed/18751909

New insights into endocannabinoid degradation and its therapeutic potential.

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Abstract

“Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipidic mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of (-)-Delta9-tetrahydrocannabinol (THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA and 2-AG at their receptors is limited by cellular uptake through an anandamide membrane transporter (AMT), followed by intracellular degradation. A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase, whereas a monoacylglycerol lipase (MAGL) is critical in degrading 2-AG. Here, we will review growing evidence that demonstrates that these hydrolases are pivotal regulators of the endogenous levels of AEA and 2-AG in vivo, overall suggesting that specific inhibitors of AMT, FAAH or MAGL may serve as attractive therapeutic targets for the treatment of human disorders. Recently, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine (NArPE), and the diacylglycerol lipase (DAGL), which generates 2-AG from diacylglycerol (DAG) substrates, have been characterized. The role of these synthetic routes in maintaining the endocannabinoid tone in vivo will be discussed. Finally, the effects of inhibitors of endocannabinoid degradation in animal models of human disease will be reviewed, with an emphasis on their ongoing applications in anxiety, cancer and neurodegenerative disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/16515464

Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors.

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Abstract

“The specific protein target of delta9-tetrahydrocannabinol (delta9-THC), the main active ingredient of Cannabis sativa L., was characterized from rat brain nearly 20 years ago, and several endogenous compounds and proteins comprising the endocannabinoid (eCB) system have since been discovered. It has become evident that the eCB system consists of at least two cannabinoid receptors (i.e. the CB1 and CB2 receptors), in addition to their endogenous ligands (the eCBs) and several enzymes involved in the biosynthesis and catabolism of the eCBs. The two well-established eCBs, N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced by neurons on demand, act near their sites of synthesis and are effectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), respectively. Inhibitors specifically targeting these enzymes could offer novel therapeutic approaches (e.g. for the treatment of pain and movement disorders). This MiniReview summarizes the literature concerning the potential therapeutic potential of FAAH and MGL inhibitors.”

http://www.ncbi.nlm.nih.gov/pubmed/17910610