New approaches and challenges to targeting the endocannabinoid system

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(9), P. 623 - 639

Published: Aug. 17, 2018

Language: Английский

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2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain

Progress in Lipid Research, Journal Year: 2018, Volume and Issue: 71, P. 1 - 17

Published: May 8, 2018

2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that key regulator of neurotransmitter release. 2-AG an endocannabinoid activates cannabinoid CB1 receptor. It involved wide array (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe biosynthetic metabolic pathways how chemical genetic perturbation these has led to insight biological role lipid. Finally, discuss potential therapeutic benefits modulating levels brain.

Language: Английский

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Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

Molecules, Journal Year: 2019, Volume and Issue: 24(5), P. 918 - 918

Published: March 6, 2019

The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, endocannabinoids (eCBs; e.g., anandamide), eCB-responsive receptors (e.g., CB₁, CB₂), as well complex enzyme and transporter apparatus involved in metabolism ligands were shown expressed several tissues, including skin. Although best studied functions ECS are related central nervous immune processes, experimental efforts last two decades have unambiguously confirmed that cutaneous cannabinoid ("c[ut]annabinoid") signaling is deeply maintenance skin homeostasis, barrier formation regeneration, its dysregulation was implicated contribute highly prevalent diseases disorders, atopic dermatitis, psoriasis, scleroderma, acne, hair growth pigmentation keratin diseases, various tumors, itch. current review aims give overview available skin-relevant endo- phytocannabinoid literature with special emphasis on putative translational potential, highlight promising future research directions existing challenges.

Language: Английский

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Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(5), P. 885 - 958

Published: May 10, 2023

The cannabis derivative marijuana is the most widely used recreational drug in Western world and consumed by an estimated 83 million individuals (∼3% of population). In recent years, there has been a marked transformation society regarding risk perception cannabis, driven its legalization medical use many states United States worldwide. Compelling research evidence Food Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed large therapeutic potential itself, Δ

Language: Английский

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The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 20, 2025

While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an "on-demand release" model, wherein formation of microvesicles, a specific group extracellular vesicles (EVs) containing eCB, 2-arachidonoylglycerol (2-AG), important step. A coculture model system combines reporter cell line expressing fluorescent eCB sensor, G protein-coupled receptor-based (GRAB)eCB2.0, cells revealed neurons EVs 2-AG, but not anandamide, in stimulus-dependent process regulated by protein kinase C, Diacylglycerol lipase, Adenosinediphosphate (ADP) ribosylation factor 6 (Arf6), which was sensitive to inhibitors facilitated diffusion. vesicle contained approximately 2,000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity modulated Arf6 inhibitors. The supported mathematical analysis, offers cohesive framework for understanding trafficking at level suggests microvesicles carrying signaling lipids membrane regulate functions parallel canonical vesicles.

Language: Английский

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Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

Frontiers in Immunology, Journal Year: 2017, Volume and Issue: 8

Published: Nov. 9, 2017

It is well known that certain active ingredients of the plants Cannabis genus, i.e., "phytocannabinoids" [pCBs; e.g., (-)-trans-Δ9-tetrahydrocannabinol (THC), (-)-cannabidiol, etc.] can influence a wide array biological processes, and human body able to produce endogenous analogs these substances ["endocannabinoids" (eCB), arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.]. These ligands, together with multiple receptors (e.g., CB1 CB2 cannabinoid receptors, etc.), complex enzyme transporter apparatus involved in synthesis degradation ligands constitute endocannabinoid system (ECS), recently emerging regulator several physiological processes. The ECS widely expressed body, including members innate adaptive immune system, where eCBs, as pCBs were shown deeply functions thereby regulating inflammation, autoimmunity, antitumor, antipathogen responses, etc. Based on this knowledge, many vitro vivo studies aimed at exploiting putative therapeutic potential signaling inflammation-accompanied diseases sclerosis) or organ transplantation, dissect immunological effects medical "recreational" marijuana consumption. Thus, objective current article (i) summarize most recent findings field; (ii) highlight targeting signaling; (iii) identify open questions key challenges; (iv) suggest promising future directions for cannabinoid-based drug development.

Language: Английский

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The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases

Progress in Neurobiology, Journal Year: 2017, Volume and Issue: 160, P. 82 - 100

Published: Oct. 31, 2017

Multiple sclerosis is the most common inflammatory demyelinating disease of central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although knowledge on its underlying neurobiological mechanisms has considerably improved, there a still unmet need for new treatment options, especially forms disease. Both preclinical clinical data suggest cannabinoids, derived from Cannabis sativa plant, may be used control symptoms such as spasticity chronic pain, whereas only indicate these compounds their endogenous counterparts, i.e. endocannabinoids, also exert neuroprotective effects slow down progression. Here, we review studies could explain therapeutic action cannabinoid-based medicines, well medical potential modulating endocannabinoid signaling in multiple sclerosis, with link other neuroinflammatory disorders share hallmarks pathogenetic features.

Language: Английский

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The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 10

Published: April 5, 2019

The endocannabinoid system has been placed in the anti-cancer spotlight last decade. immense data load published on its dual role both tumourigenesis and inhibition of tumour growth metastatic spread transformed cannabinoid receptors CB1 (CB1R) CB2 (CB2R), as well other members endocannabinoid-like system, into attractive new targets for treatment various cancer subtypes. Although clinical use cannabinoids extensively documented palliative setting, trials their application drugs are still ongoing. As drug repurposing is significantly faster more economical than de novo introduction a clinic, there hope that existing pharmacokinetic safety ligands will contribute to successful translation oncological healthcare. CB1R CB2R belong G protein-coupled receptor (GPCR) superfamily membrane proteins. GPCRs have found form homodimers, heterodimers higher order oligomers with or non-GPCRs. Currently, several CB2R-containing heteromers reported and, cells, 55 (GPR55) tyrosine kinase (TKR) human V-Erb-B2 Avian Erythroblastic Leukaemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological signalling properties, modulation might affect antitumoural activity system. This review explore potential network setting ethical pitfalls behind it, develop value therapies prognostic biomarkers.

Language: Английский

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Endocannabinoid System Components as Potential Biomarkers in Psychiatry

Frontiers in Psychiatry, Journal Year: 2020, Volume and Issue: 11

Published: April 27, 2020

The high heterogeneity of psychiatric disorders, leads to a lack diagnostic precision. Therefore, the search biomarkers is fundamental aspect in psychiatry reach more personalized medicine. endocannabinoid system (ECS) has gained increasing interest due its involvement many different functional processes brain, including regulation emotions, motivation and cognition. This article reviews role main components ECS as certain disorders. Studies carried out rodents evaluating effects pharmacological genetic manipulation cannabinoid receptors or endocannabinoids (eCBs) degrading enzymes. Likewise, ECS-related alterations occurring at molecular level animal models reproducing some behavioral and/or neuropathological aspects disorders were reviewed. Clinical studies gene protein post-mortem brain tissue vivo blood, plasma cerebrospinal fluid (CSF) samples analyzed. Furthermore, results from neuroimaging using positron emission tomography (PET) magnetic resonance (fMRI) included. review shows close receptor 1 (CB1r) stress development mood (anxiety, depression, bipolar disorder (BD)), post-traumatic (PTSD), well etiopathogenesis schizophrenia, attention deficit hyperactivity (ADHD) eating (i.e. anorexia bulimia nervosa). On other hand, recent regarding potential therapeutic action tone by inhibition eCBs enzymes, modulation 2 (CB2r) activity on anxiolytic, antidepressive antipsychotic associated Further clinical research are needed, however, current evidence suggests that may become promising improve, least part, diagnosis treatment

Language: Английский

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Monoacylglycerol lipase (MAGL) as a promising therapeutic target

Biochemical Pharmacology, Journal Year: 2018, Volume and Issue: 157, P. 18 - 32

Published: July 27, 2018

Language: Английский

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