Tag Archives: endocannabinoids

The Endocannabinoid System Is Present in Rod Outer Segments from Retina and Is Modulated by Light.

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“The aim of the present research was to evaluate if the endocannabinoid system (enzymes and receptors) could be modulated by light in rod outer segment (ROS) from bovine retina. First, we analyzed endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in purified ROS obtained from dark-adapted (DROS) or light-adapted (LROS) retinas. To this end, diacylglycerol lipase (DAGL), monoacylglycerol lipase (MAGL), and lysophosphatidate phosphohydrolase (LPAP) enzymatic activities were analyzed using radioactive substrates. The protein content of these enzymes and of the receptors to which cannabinoids bind was determined by immunoblotting under light stimulus. Our results indicate that whereas DAGL and MAGL activities were stimulated in retinas exposed to light, no changes were observed in LPAP activity. Interestingly, the protein content of the main enzymes involved in 2-AG metabolism, phospholipase C β1 (PLCβ1), and DAGLα (synthesis), and MAGL (hydrolysis), was also modified by light. PLCβ1 content was increased, while that of lipases was decreased. On the other hand, light produced an increase in the cannabinoid receptors CB1 and CB2 and a decrease in GPR55 protein levels. Taken together, our results indicate that the endocannabinoid system (enzymes and receptors) depends on the illumination state of the retina, suggesting that proteins related to phototransduction phenomena could be involved in the effects observed.”

https://www.ncbi.nlm.nih.gov/pubmed/31016476

https://link.springer.com/article/10.1007%2Fs12035-019-1603-5

Cannabinoid Regulation of Fear and Anxiety: an Update.

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“Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

RECENT FINDINGS:

Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/31030284

https://link.springer.com/article/10.1007%2Fs11920-019-1026-z

The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma.

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“Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.”

https://www.ncbi.nlm.nih.gov/pubmed/31003519

https://www.mdpi.com/1422-0067/20/8/1919

Circulating endocannabinoid concentrations and sexual arousal in women.

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The Journal of Sexual Medicine - Click here to go back to the homepage

“Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species.

AIM:

To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (N = 21).

METHODS:

Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and noncontinuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal.

MAIN OUTCOME MEASURES:

Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal.

RESULTS:

Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of sexual arousal were significantly associated with decreases in 2-AG.

CONCLUSIONS:

These findings support the hypothesis that the endocannabinoid system is involved in female sexual functioning, with implications for furthering understanding of the biological mechanisms underlying female sexual functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/22462722

https://www.jsm.jsexmed.org/article/S1743-6095(15)33996-5/fulltext

[Significance of the endocannabinoid system in migraine].

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“Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoid like system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endocannabinoid dysfunction, namely endocannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endocannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endocannabinoid system may be a potential drug target in the migraine therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30962405

Treatment of Fragile X Syndrome with Cannabidiol: A Case Series Study and Brief Review of the Literature.

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“Fragile X syndrome (FXS) is an X-linked dominant disorder caused by a mutation in the fragile X mental retardation 1 gene.

Cannabidiol (CBD) is an exogenous phytocannabinoid with therapeutic potential for individuals with anxiety, poor sleep, and cognitive deficits, as well as populations with endocannabinoid deficiencies, such as those who suffer from FXS.

The objective of this study was to provide a brief narrative review of recent literature on endocannabinoids and FXS and to present a case series describing three patients with FXS who were treated with oral CBD-enriched (CBD+) solutions.

We review recent animal and human studies of endocannabinoids in FXS and present the cases of one child and two adults with FXS who were treated with various oral botanical CBD+ solutions delivering doses of 32.0 to 63.9 mg daily. Multiple experimental and clinical models of FXS combine to highlight the therapeutic potential of CBD for management of FXS.

All three patients described in the case series exhibited functional benefit following the use of oral CBD+ solutions, including noticeable reductions in social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing. Two of the described patients exhibited a reemergence of a number of FXS symptoms following cessation of CBD+ treatment (e.g., anxiety), which then improved again after reintroduction of CBD+ treatment. Findings highlight the importance of exploring the therapeutic potential of CBD within the context of rigorous clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/30944868
“The present findings, coupled with the available preclinical data, highlight the potential for CBD as an intervention for individuals with FXS. The existing literature combines to demonstrate that CBD may positively impact individuals with FXS through many mechanisms, including the endocannabinoid system, GABA, and serotonin. While a number of drugs have been developed to target specific systems (e.g., GABA agonists), CBD has the potential to yield a multifaceted benefit to individuals with FXS due to its multiple mechanisms of action.”
https://www.liebertpub.com/doi/10.1089/can.2018.0053

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

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Neuropharmacology

“Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington’s disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoidsystem in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30914306

https://www.sciencedirect.com/science/article/pii/S0028390819301066?via%3Dihub

In-silico designing and characterization of binding modes of two novel inhibitors for CB1 receptor against obesity by classical 3D-QSAR approach.

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Journal of Molecular Graphics and Modelling

“Obesity is the fifth primary hazard for mortality in the world; hence different therapeutic targets are explored to overcome this problem.

Endocannabinoid is identified as the emerging target for the treatment of obesity as Cannabinoid 1 (CB1) receptor over-activation resulted in abdominal obesity.

Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs.

The obtained results signify the potential of the developed model; suggesting that the models can be useful to test and design potent novel CB1 receptor antagonists or inverse agonists prior to the synthesis.”

https://www.ncbi.nlm.nih.gov/pubmed/30908997

“Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs.”

https://www.sciencedirect.com/science/article/pii/S1093326318308398?via%3Dihub

Cannabinoid CB2R receptors are upregulated with corneal injury and regulate the course of corneal wound healing.

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Experimental Eye Research

“CB2R receptors have demonstrated beneficial effects in wound healing in several models. We therefore investigated a potential role of CB2R receptors in corneal wound healing. We examined the functional contribution of CB2R receptors to the course of wound closure in an in vivo murine model. We additionally examined corneal expression of CB2R receptors in mouse and the consequences of their activation on cellular signaling, migration and proliferation in cultured bovine corneal epithelial cells (CECs). Using a novel mouse model, we provide evidence that corneal injury increases CB2R receptor expression in cornea. The CB2R agonist JWH133 induces chemorepulsion in cultured bovine CECs but does not alter CEC proliferation. The signaling profile of CB2R activation is activating MAPK and increasing cAMP accumulation, the latter perhaps due to Gs-coupling. Lipidomic analysis in bovine cornea shows a rise in acylethanolamines including the endocannabinoid anandamide 1 h after injury. In vivo, CB2R deletion and pharmacological block result in a delayed course of wound closure. In summary, we find evidence that CB2R receptor promoter activity is increased by corneal injury and that these receptors are required for the normal course of wound closure, possibly via chemorepulsion.”

https://www.ncbi.nlm.nih.gov/pubmed/30905716

https://www.sciencedirect.com/science/article/pii/S0014483518307206?via%3Dihub

Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders.

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“Autism spectrum disorders (ASDs) are diagnosed on the basis of three behavioral features, namely, (1) deficits in social communication, (2) absence or delay in language and (3) stereotypy. The consensus regarding the neurological pathogenesis of ASDs is aberrant synaptogenesis and synapse function. Further, it is now widely accepted that ASD is neurodevelopmental in nature, placing emphasis on derangements occurring at the level of intra- and intercellular signaling during corticogenesis. At present, there is an ever-growing list of mutations in putative susceptibility genes in affected individuals, preventing effective transformation of knowledge gathered from basic science research to the clinic. In response, the focus of ASD biology has shifted toward the identification of cellular signaling pathways that are common to various ASD-related mutations in hopes that these shared pathways may serve as more promising treatment targets than targeting individual genes or proteins. To this end, the endogenous cannabinoid (endocannabinoid, eCB) system has recently emerged as a promising therapeutic target in the field of ASD research. The eCB system is altered in several neurological disorders, but the role of these bioactive lipids in ASD etiology remains poorly understood. In this perspective, we review current evidence linking eCB signaling to ASDs and put forth the notion that continued focus on eCBs in autism research may provide valuable insight into pathophysiology and treatment strategies. In addition to its role in modulating transmitter release at mature synapses, the eCB signaling system plays important roles in many aspects of cortical development, and disruption of these effects of eCBs may also be related to ASD pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30854511

“Advances in our understanding of eCB actions will undoubtedly facilitate pharmacological interventions and further, provide patients the best quality of life possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407886/