A comprehensive review of the multifaceted role of cannabinoid receptor type 2 in neurodegenerative and neuropsychiatric disorders

Pharmacological Research, Journal Year: 2025, Volume and Issue: 213, P. 107657 - 107657

Published: Feb. 19, 2025

Research carried out during the last 30 years since first identification of CB2r in 1993 has changed landscape this receptor's role and therapeutic utility. Initially, studies focused on elucidating at periphery it was characterized spleen lymphocytes. Later, found brain not only under pathological conditions but also basal conditions. It is now known that receptor expressed different regions cell types, including neurons microglia. Experimental have provided robust evidence involved modulation immune system, neuroinflammation, oxidative stress neuroprotection. Besides, mediated response to stress, anxiety, depression. Also, plays a relevant modulating reinforcing properties drugs abuse, alcohol, nicotine cocaine. In review, we summarize cumulative knowledge regarding immunomodulatory, anti-inflammatory, antioxidant, neuroprotective against development neurodegenerative diseases. Indeed, cover anxiolytic antidepressant potential CB2r, which raises interest psychiatric diseases associated with anxiety Finally, discuss involvement regulation drug addiction. A better understanding essential for pharmacological neurodegenerative, psychiatric, addictive disorders.

Language: Английский

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CB2 receptor in the CNS: From immune and neuronal modulation to behavior

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 150, P. 105226 - 105226

Published: May 8, 2023

Language: Английский

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MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

Theranostics, Journal Year: 2024, Volume and Issue: 14(4), P. 1583 - 1601

Published: Jan. 1, 2024

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD).Tubular cell injury plays pivotal role renal fibrosis.Commonly, injured tubular cells exhibit significant lipid accumulation.However, the underlying mechanisms remain poorly understood.Methods: 2-arachidonoylglycerol (2-AG) levels CKD patients and model specimens were measured using mass spectrometry.2-AG-loaded nanoparticles infused into unilateral ureteral obstruction (UUO) mice.Lipid accumulation fibrosis tested.Furthermore, monoacylglycerol lipase (MAGL), hydrolyzing enzyme of 2-AG, was assessed models.Tubular cell-specific MAGL knock-in mice generated.Moreover, recombination protein also administered to ischemia reperfusion (UIRI) mice.Besides, series methods including RNA sequencing, metabolomics, primary culture, staining, etc. used.Results: 2-AG increased serum or kidneys from models.Supplement further induced fibrogenesis through cannabinoid receptor type 2 (CB2)/β-catenin signaling.β-catenin knockout blocked 2-AG/CB2-induced fatty acid β-oxidation (FAO) deficiency accumulation.Remarkably, significantly decreased CKD, aligning fibrosis.Specific transgene preserved FAO, inhibited lipid-mediated toxicity cells, finally retarded fibrogenesis.Additionally, supplementation UIRI FAO function, accumulation, protected against fibrosis.Conclusion: potential diagnostic marker for function decline, serves as new target ameliorating lipotoxicity.

Language: Английский

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Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies

Frontiers in Neuroendocrinology, Journal Year: 2023, Volume and Issue: 69, P. 101066 - 101066

Published: April 1, 2023

Orexins (also known as hypocretins) are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system and bind two different G protein-coupled receptors (OX1R OX2R). Since its discovery 1998, orexin has gained interest of scientific community a potential therapeutic target for treatment pathological conditions. Considering previous basic science research, dual receptor antagonist, suvorexant, was first agent to be approved by US Food Drug Administration treat insomnia. In this review, we discuss update main preclinical human studies involving with several psychiatric neurodegenerative diseases. This constitutes nice example how research driven curiosity can best route generation new powerful pharmacological treatments.

Language: Английский

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Molecular Insights into Epigenetics and Cannabinoid Receptors

Biomolecules, Journal Year: 2022, Volume and Issue: 12(11), P. 1560 - 1560

Published: Oct. 26, 2022

The actions of cannabis are mediated by G protein-coupled receptors that part an endogenous cannabinoid system (ECS). ECS consists the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic degradative enzymes, CB1 CB2 receptors. Epigenetics heritable changes affect gene expression without changing DNA sequence, transducing external stimuli in stable alterations or chromatin structure. Cannabinoid crucial candidates for exploring functions through epigenetic approaches due to significant roles health diseases. Epigenetic usually promote genes proteins can be evaluated various transcriptomic proteomic analyses. Despite exponential growth new evidence on critical receptors, much is still unknown regarding contribution genetic factors regulate receptor expression. Recent studies have identified several immediate long-lasting changes, such as methylation, DNA-associated histone proteins, RNA regulatory networks, function. Thus, they offer solutions many cellular, molecular, behavioral impairments found after modulation activities. In this review, we discuss research advances different contributing regulation under both physiological pathological conditions. Increasing our understanding epigenetics will significantly advance knowledge could lead identification novel therapeutic targets innovative treatment strategies diseases associated with altered functions.

Language: Английский

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Antagonization of OX1 Receptor Potentiates CB2 Receptor Function in Microglia from APPSw/Ind Mice Model

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12801 - 12801

Published: Oct. 24, 2022

Microdialysis assays demonstrated a possible role of orexin in the regulation amyloid beta peptide (Aß) levels hippocampal interstitial fluid APP transgenic model. CB2R is overexpressed activated microglia, showing neuroprotective effect. These two receptors may interact, forming CB2-OX1-Hets and becoming new target to combat Alzheimer's disease. Aims: Demonstrate potential expression function microglia from animal models Receptor heteromer was detected by immunocytochemistry, bioluminescence resonance energy transfer (BRET) proximity ligation assay (PLA) transfected HEK-293T cells primary cultures. Quantitation signal transduction events heterologous system performed using AlphaScreen® SureFire® kit, western blot, GCaMP6 calcium sensor Lance Ultra cAMP kit (PerkinElmer). The formation CB2-OX1 receptor complexes has been demonstrated. tetrameric complex constituted one homodimer, OX1R homodimer G proteins, Gi Gq. use TAT interfering peptides showed that interface TM4-TM5. At functional level it observed antagonist, SB334867, potentiates action induced agonist JWH133. This effect stronger disease (AD) model APPSw/Ind where assessed indicates an increase number compared resting microglia. AD antagonists potentiate actions activation. Taken together, these results point as drugs with therapeutic AD. Data access statement: Raw data will be provided corresponding author upon reasonable requirement.

Language: Английский

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Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity

Molecular Metabolism, Journal Year: 2023, Volume and Issue: 72, P. 101713 - 101713

Published: March 26, 2023

Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology regulating energy homeostasis complex behaviors linked to arousal. Under conditions chronic or acute leptin signaling deficiency, such as in obesity short-term food deprivation, respectively, OX-A become hyperactive promote hyperarousal seeking. However, this leptin-dependent mechanism still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) known be implicated consumption promoting hyperphagia obesity, we others demonstrated that strong inducer 2-AG biosynthesis. Here, investigated hypothesis that, under (6 h fasting wt mice) (in ob/ob hypothalamic reduction, OX-A-induced enhancement levels leads production 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), bioactive lipid belonging class lysophosphatidic acids (LPAs), which then regulates synaptic plasticity disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting intake.We combined cell-type-specific morphological (CLEM confocal microscopy), biochemical, pharmacological, electrophysiological techniques dissect leptin- OX-A/2-AGP-mediated molecular pathways GSK-3β-controlled pT231-Tau at POMC obese wild-type (wt) lean littermate mice an vitro model mHypoN41 (N41).2-AGP overproduced hypothalamus leptin-deficient, 6 food-deprived mice, promotes intake reducing α-MSH-expressing acid type-1 receptor (LPA1-R) activation, accumulation projections. This effect due activation Pyk2-mediated pTyr216-GSK3β pathway contributes further elevating release obesity. Accordingly, found correlation between 2-AGP serum human subjects.Hypothalamic feeding are endowed with 2-AGP-mediated according their inherent functional activities necessity adapt changes nutritional status. These findings reveal new involved regulation, could targeted treat related disturbances.

Language: Английский

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Identification of a novel fatty acid binding protein-5-CB2 receptor-dependent mechanism regulating anxiety behaviors in the prefrontal cortex

Cerebral Cortex, Journal Year: 2022, Volume and Issue: 33(6), P. 2470 - 2484

Published: June 1, 2022

Abstract The endocannabinoid (eCB) system represents a promising neurobiological target for novel anxiolytic pharmacotherapies. Previous clinical and preclinical evidence has revealed that genetic and/or pharmacological manipulations altering eCB signaling modulate fear anxiety behaviors. Water-insoluble lipid anandamide requires chaperone proteins its intracellular transport to degradation, process fatty acid-binding (FABPs). Here, we investigated the effects of FABP-5 inhibitor, SBFI-103, on anxiety-related behaviors using rats. Acute intra-prelimbic cortex administration SBFI-103 induced dose-dependent response reduced contextual expression. Surprisingly, both were reversed when cannabinoid-2 receptor (CB2R) antagonist, AM630, was co-infused with SBFI-103. Co-infusion cannabinoid-1 antagonist Rimonabant yet showed no reversal effect anxiety. Furthermore, in vivo neuronal recordings region infusion altered activity putative pyramidal neurons basolateral amygdala ventral hippocampus, as well oscillatory patterns within these regions CB2R-dependent fashion. Our findings identify role FABP5 inhibition potential pharmacotherapy. novel, pathway PFC capable strongly modulating transmission patterns.

Language: Английский

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Editorial: Targeting the endocannabinoidome in neurodegenerative disorders

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 4, 2023

EDITORIAL article Front. Aging Neurosci., 04 January 2023Sec. Cellular and Molecular Mechanisms of Brain-aging Volume 14 - 2022 | https://doi.org/10.3389/fnagi.2022.1116635

Language: Английский

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Endocannabinoid Receptor 2 Function is Associated with Tumor-Associated Macrophage Accumulation and Increases in T Cell Number to Initiate a Potent Antitumor Response in a Syngeneic Murine Model of Glioblastoma

Cannabis and Cannabinoid Research, Journal Year: 2024, Volume and Issue: unknown

Published: June 18, 2024

Glioblastoma patients have a highly immunosuppressive tumor microenvironment and systemic immunosuppression that comprise major barrier to immune checkpoint therapy. Based on the production of endocannabinoids by glioblastomas, we explored involvement endocannabinoid receptor 2 (CB2R), encoded CNR2 gene, which is predominantly expressed cells, in glioblastoma-related immunosuppression.

Language: Английский

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