Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice.

Seizure - European Journal of Epilepsy Home

“Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy.

Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice.


Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.”

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”

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Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures.

Metabolic Brain Disease

“2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways.

Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism.

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.”

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The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization.

Journal of Neuroimmunology

“Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist SR141716A. Our study demonstrated that SR141716A accelerated the clinical onset and development of EAE, accompanied by body weight loss. SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and nuclear factor-kappaB/p65 (NF-κB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-α, IL-1β, IL-6) and chemokines (MCP-1, CX3CL1), accompanied by the shifts of cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-γ)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except chemokine CX3CL1. Consistently, SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-α, IL-1β, IL-6) while inhibited the production of IL-10 and chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of IL-4 and IL-10 were decreased while production of IL-17 and IFN-γ increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-κB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application.”

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β-Amyrin, the cannabinoid receptors agonist, abrogates mice brain microglial cells inflammation induced by lipopolysaccharide/interferon-γ and regulates Mφ1/Mφ2 balances.

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“Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases.

The purpose of this study was to evaluate the effect of β-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells.


β-Amyrin reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system neurodegenerative diseases such as Alzheimer and multiple sclerosis, by affecting the inflammatory cytokine and differentiation of microglia as resident CNS macrophages.”

“Amyrin and the endocannabinoid system. The canonical triterpene amyrin was recently suggested to bind to CB1 receptors and to significantly mediate cannabimimetic effects in animal models of pain.”

“The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting CB receptors”

“Finally, pentacyclic triterpenes such as β-amyrin and cycloartenol have been shown to possess numerous biological activities including anti-bacterial, anti-fungal, anti-inflammatory and anti-cancer properties.”

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Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets.


“The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell.

To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism.


Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes.”

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Role of cannabinoid receptor type 1 in rostral ventrolateral medulla in high-fat diet-induced hypertension in rats.

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“Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that CB1 receptor in the RVLM may play a critical role in the development of obesity-induced hypertension.


To this end, we evaluated the levels of endocannabinoids and CB1 receptors in the RVLM in high-fat diet (HFD)-induced hypertensive rats. We then used pharmacological and molecular methods to examine the role of RVLM CB1 receptors in regulation of BP, heart rate (HR), and RSNA in obesity-induced hypertensive rats.


We found that HFD-fed rats exhibited higher basal BP, HR, and RSNA than standard diet-fed rats, which were associated with increased levels of endocannabinoids and CB1 receptor expression in the RVLM. Furthermore, unilateral intra-RVLM microinjections of AM251 (0, 100, or 500 nM/0.5 μl/site) dose-dependently decreased BP, HR, and RSNA to a greater extent in HFD-fed rats than in standard diet-fed rats. Finally, siRNA-mediated knockdown of CB1 receptor expression in the RVLM robustly decreased BP, HR, and RSNA in HFD-fed rats.


Taken together, our results suggested that enhanced CB1 receptor-mediated neurotransmissions in the RVLM may play a role in the development of obesity-induced hypertension.”

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The Role of Cannabinoid Receptor 1 in the Immunopathology of Respiratory Syncytial Virus.

Mary Ann Liebert, Inc. publishers

“Endocannabinoid system plays an important role in pathophysiologic processes such as immune functions and impacts on disease severity.

Our previous study showed that cannabinoid receptor 2 (CB2) affects clinical course of respiratory syncytial virus (RSV) infection. In this study, we investigated the role of cannabinoid receptor 1 (CB1) in RSV immunopathology and its therapeutic potential in mice model.

This study and our previous finding indicated that endocannabinoid signaling regulates the inflammatory response to RSV infection, and is a potential therapeutic candidate for alleviation of RSV-associated immunopathology.”

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Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.

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“Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management.

A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response.

We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R).

Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing.

Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls.

This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.”

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Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats.

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“Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED). Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats.

For this purpose, brain levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus).

The brain density of cannabinoid type-1 receptors (CB1) was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain.

To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD) (margarine). Three experimental groups were used, all with ad libitum access to chow: control (CTRL), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days/week; high restriction (HR), with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group.

Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both ghrelin and corticosterone levels, while leptin remained unaltered.

In conclusion, our findings show a modified endocannabinoid tone due to margarine exposure, in several brain areas that are known to influence the hedonic aspect of food. Even if not uniquely specific to binge eating, margarine-induced changes in endocannabinoid tone could contributes to the development and maintenance of this behavior.”

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Role of the Endocannabinoid System in the Neurobiology of Suicide

Cover of The Neurobiological Basis of Suicide

“In the past decade, remarkable advances have been made in cannabinoid (CB) research. The brain endocannabinoid (eCB) system modulates several neurobiological processes and its dysfunction is suggested to be involved in the pathophysiology of mood and drug use disorders.

The CB1 receptor–mediated signaling, in particular, has been shown to play a critical role in the neural circuitry that mediates mood, motivation, and emotional behaviors. This chapter presents the data pertaining to the involvement of the eCB system in depression, suicide, and alcohol addiction.

It appears that the eCB system might have a critical role in the regulation of mood and emotional responses that are impaired in patients with depression and suicidal behavior.

The data provided in this chapter support the notion that the eCB system might be an additional target for the development of a drug against alcohol use, depression, and suicidal behavior.

Among therapeutic agents, antidepressants are the most widely used drugs for the treatment of depression-related disorders.”

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from cannabis sativa L. The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. Results of this study show that Δ9-THC and other cannabinoids exert anti-depressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”

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