Tag Archives: endocannabinoid system

Human Cannabinoid Receptor 2 Ligand-interaction Motif: Transmembrane Helix 2 Cysteine, C2.59(89), as Determinant of Classical Cannabinoid Agonist Activity and Binding Pose.

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“Cannabinoid receptor 2 (CB2R)-dependent signaling is implicated in neuronal physiology and immune surveillance by brain microglia. Selective CB2R agonists hold therapeutic promise for inflammatory and other neurological disorders.

Information on human CB2R (hCB2R) ligand-binding and functional domains is needed to inform the rational design and optimization of candidate drug-like hCB2R agonists.

These data constitute initial evidence that TMH2 cysteine C2.59(89) is a component of the hCB2R binding pocket for classical cannabinoids.

The results further demonstrate how interactions between classical cannabinoids and specific amino acids within the hCB2R* ligand-binding domain act as determinants of agonist pharmacological properties and the architecture of the agonist-hCB2R* conformational ensemble, allowing the receptor to adopt distinct activity states, such that interaction of classical cannabinoids with TMH6 cysteine C6.47(257) favors a binding pose more advantageous for agonist potency than does their interaction with TMH2 cysteine C2.59(89).”

 https://www.ncbi.nlm.nih.gov/pubmed/28220706

Brain cannabinoid systems as targets for the therapy of neurological disorders.

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“Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.” https://www.ncbi.nlm.nih.gov/pubmed/9974182 

“Endocannabinoid System in Neurological Disorders.” https://www.ncbi.nlm.nih.gov/pubmed/27364363
 
“Cannabinoids in the Treatment of Neurological Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604187/

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

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“Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans.

We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice.

 Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

In conclusion, the current study provides the first evidence that the eCB system may contribute to severe obesity both in PWS children and adults and in an established mouse model for this syndrome. Our results confirm that the eCB system contributes to the metabolic phenotype associated with PWS. Moreover, specifically targeting the peripheral eCB system in obese Magel2-null mice was found to be as efficacious as in DIO animals, and, therefore, it may represent a novel approach to treating obesity and its complications in PWS. This would also provide the rationale for the development and clinical testing of peripherally restricted CB1R antagonists for treating obesity in PWS.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123200/

“Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.” https://www.ncbi.nlm.nih.gov/pubmed/22335400

“The phytocannabinoid, Delta(9)-tetrahydrocannabivarin (THCV), can block cannabinoid CB(1) receptors” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931567/

Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target.

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“As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically.

Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis.

In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration.

For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28210207

“Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020102/

“The influence of cannabinoids on generic traits of neurodegeneration.  Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954477/

 

Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice.

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“The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines.

The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation.

We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination.

We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response.

Here we demonstrate, for the first time, that transient administration of the cannabinoid receptor 2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightens the intensity and breadth of antigen-specific immune responses in young and aged mice through the upregulation of immunomodulatory genes in secondary lymphoid tissues.”

 https://www.ncbi.nlm.nih.gov/pubmed/28209996

Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype.

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“Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions.

Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress.

In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling.

Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects.

Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype.

Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses.”

https://www.ncbi.nlm.nih.gov/pubmed/28209423

Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?

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“Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.”  https://www.ncbi.nlm.nih.gov/pubmed/28197175

“The endocannabinoid system in amyotrophic lateral sclerosis. There is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors. The ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS.” http://www.ncbi.nlm.nih.gov/pubmed/18781981

“Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis (ALS). Our data suggest that cannabinoid CB1 receptors might be potential therapeutic targets for this dramatic disease.” http://www.ncbi.nlm.nih.gov/pubmed/19452308

“Cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.” http://www.ncbi.nlm.nih.gov/pubmed/16781706

“Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. The cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.” http://www.ncbi.nlm.nih.gov/pubmed/15204022

“Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive constituent in the plant Cannabis sativa (marijuana) and produces its effects by activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) cannabinoid receptors. Administration of the non-selective partial cannabinoid agonists Δ9-THC or cannabinol are successful in delaying motor impairment and prolonging survival in mice after the onset of symptoms. Collectively, these studies suggest that cannabinoid receptors might serve as novel therapeutic targets for ALS drug development. CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819701/

“Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS)” http://www.ncbi.nlm.nih.gov/pubmed/22594565

“Therapeutic options for amyotrophic lateral sclerosis (ALS) remain limited. Evidence suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. We found that this treatment significantly delays disease onset. Cannabinoids might be useful in ameliorating symptoms in ALS.” http://www.ncbi.nlm.nih.gov/pubmed/16183560

“Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects. Marijuana should be considered in the pharmacological management of ALS.” http://www.ncbi.nlm.nih.gov/pubmed/11467101

“Ideally, a multidrug regimen would be required to comprehensively address the known pathophysiology of ALS. REMARKABLY, cannabis appears to have activity in all of those areas. Cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. Cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.” http://www.ncbi.nlm.nih.gov/pubmed/20439484

“In light of the above findings, there is a valid rationale to propose the use of cannabinoid compounds in the pharmacological management of ALS patients. Cannabinoids indeed are able to delay ALS progression and prolong survival.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270417/

http://www.thctotalhealthcare.com/category/amyotrophic-lateral-sclerosis-als-lou-gehrigs-disease/

Pharmacological inhibition of MAGL lipase attenuates experimental colon carcinogenesis.

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“Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells.

Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells.

Here, we investigated the role of MAGL in experimental colon carcinogenesis.

MAGL, possibly through modulation of angiogenesis, plays a pivotal role in experimental colon carcinogenesis.

Pharmacological inhibition of MAGL could represent an innovative therapeutic approach to reduce colorectal tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/28193521

Differential Expression of Endocannabinoid System-Related Genes in the Dorsal Hippocampus following Expression and Reinstatement of Morphine Conditioned Place Preference in Mice.

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“The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine.

Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation. To test this possibility, we systematically compared the expression of eCB-related genes in the dorsal hippocampus following the expression, extinction, and reinstatement of morphine CPP using quantitative RT-PCR analyses.

These results suggest that differential regulation of the synthesis and/or degradation of the eCB system contribute to the expression and reinstatement of morphine CPP.”

https://www.ncbi.nlm.nih.gov/pubmed/28192193

Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs.

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“Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes.

Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage.

We employed wide frequency range (0.1-300 Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction.

To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied.

Our results demonstrate the protective potential of the eCB system during excitotoxic influences.”

https://www.ncbi.nlm.nih.gov/pubmed/28192082