Tag Archives: cannabinoid receptors

The proposed mechanism of action of CBD in epilepsy.

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Image result for Epileptic Disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials.

While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy.

Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

 https://www.ncbi.nlm.nih.gov/pubmed/31919042
https://www.jle.com/fr/revues/epd/e-docs/the_proposed_mechanism_of_action_of_cbd_in_epilepsy_316039/article.phtml

Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

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Image result for Springer Link“The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.

OBJECTIVES:

This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.

METHODS:

A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH.

RESULTS:

The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH.

CONCLUSION:

These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.”

https://www.ncbi.nlm.nih.gov/pubmed/31919563

https://link.springer.com/article/10.1007%2Fs00213-019-05435-5

“panicolytic: That reduces the flight reflex in animals when faced with danger. Any drug that has this effect.” https://en.wiktionary.org/wiki/panicolytic

Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer’s Disease Lymphoblast Alterations.

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“Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including senile plaques, neurofibrillary tangles, and neuronal loss.

There are no disease-modifying drugs currently available. With the number of affected individuals increasing dramatically throughout the world, there is obvious urgent need for effective treatment strategy for AD.

The multifactorial nature of AD encouraged the development of multifunctional compounds, able to interact with several putative targets. Here, we have evaluated the effects of two in-house designed cannabinoid receptors (CB) agonists showing inhibitory actions on β-secretase-1 (BACE-1) (NP137) and BACE-1/butyrylcholinesterase (BuChE) (NP148), on cellular models of AD, including immortalized lymphocytes from late-onset AD patients.

We report here that NP137 and NP148 showed neuroprotective effects in amyloid-β-treated primary cortical neurons, and NP137 in particular rescued the cognitive deficit of TgAPP mice. The latter compound was able to blunt the abnormal cell response to serum addition or withdrawal of lymphoblasts derived from AD patients.

It is suggested that NP137 could be a good drug candidate for future treatment of AD.”

https://www.ncbi.nlm.nih.gov/pubmed/31898159

https://link.springer.com/article/10.1007%2Fs12035-019-01813-4

“The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway.” http://www.ncbi.nlm.nih.gov/pubmed/25147120

“These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.” http://www.ncbi.nlm.nih.gov/pubmed/25024327

“In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD” http://www.ncbi.nlm.nih.gov/pubmed/25147120

“Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.” http://www.ncbi.nlm.nih.gov/pubmed/15728830

“Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects.” http://www.ncbi.nlm.nih.gov/pubmed/22448595

“CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy.” http://www.ncbi.nlm.nih.gov/pubmed/27471947

The Endocannabinoid System and Synthetic Cannabinoids in Preclinical Models of Seizure and Epilepsy.

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 Related image“Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs).

Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy.

The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy.

SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure.

This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31895186

https://insights.ovid.com/crossref?an=00004691-202001000-00004

CB2R orchestrates neuronal autophagy through regulation of the mTOR signaling pathway in the hippocampus of developing rats with status epilepticus.

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 Journal Cover“Neuronal loss and gliosis are the major pathological changes after status epilepticus (SE).

The authors’ previous study revealed the time‑dependent changes of cannabinoid receptor type 2 (CB2R) in hippocampal neurons of developing rats after SE, which were accompanied by a decrease in the number of neurons. Meanwhile, growing evidence indicates that CB2R stimulation exerts anti‑convulsant properties in seizure models. However, the activation of CB2R in neuronal repair in response to the damage after SE is still unclear.

In this experiment, a highly‑selective CB2R agonist JWH133 and antagonist AM630 were administered to determine the activity of CB2R in neuronal autophagy and apoptosis of the post‑SE repair in developing rats. The present results revealed that activation of CB2R by JWH133, not only obviously lowered the success rate, 24‑h death rate and the Racine stage in the model, but also extended the latency period to SE. In addition, compared with the vehicle control group, CB2R activation increased neuronal autophagy and the expression of phosphorylated‑mammalian target of rapamycin (p‑mTOR)/mTOR, Beclin‑1, and LC3II/LC3I while decreasing the expression of p‑Unc‑51‑like autophagy‑activating kinase 1 (ULK‑1)/ULK1, p62, and cleaved caspase‑3.

These results were dose‑dependent and were especially evident in the high‑dose group, and interestingly the opposite results were obtained in the AM630 group. Thus, CB2R orchestrates neuronal autophagy through regulation of the mTOR signaling pathway in the hippocampus of developing rats with SE. These findings might provide an important basis for further investigation of the therapeutic role of CB2R in ameliorating epilepsy‑related neuronal damage.”

https://www.ncbi.nlm.nih.gov/pubmed/31894322

https://www.spandidos-publications.com/10.3892/ijmm.2019.4439

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

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molecules-logo “Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs.

Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence.

Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain.

BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31892132

https://www.mdpi.com/1420-3049/25/1/106

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Beta‐caryophyllene, a dietary terpenoid, inhibits nicotine‐taking and nicotine‐seeking in rodents

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British Journal of Pharmacology banner“Beta-caryophyllene (BCP) is a dietary plant-derived terpenoid that has been used as a food additive for many decades.

Recent studies indicate that BCP is a cannabinoid CB2 receptor (CB2R) agonist with medical benefits for a number of human diseases. However, little is known about its therapeutic potential for drug abuse and addiction.

The present findings suggest that BCP has significant anti-nicotine effects via both CB2 and non-CB2 receptor mechanisms, and therefore, deserves further study as a potential new pharmacotherapy for cigarette smoking cessation.”

https://www.ncbi.nlm.nih.gov/pubmed/31883107

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14969

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Isolation of a High-Affinity Cannabinoid for the Human CB1 Receptor from a Medicinal Cannabis sativa Variety: Δ9-Tetrahydrocannabutol, the Butyl Homologue of Δ9-Tetrahydrocannabinol.

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Go to Volume 0, Issue 0“The butyl homologues of Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabutol (Δ9-THCB), and cannabidiol, cannabidibutol (CBDB), were isolated from a medicinal Cannabis sativa variety (FM2) inflorescence. Appropriate spectroscopic and spectrometric characterization, including NMR, UV, IR, ECD, and HRMS, was carried out on both cannabinoids. The chemical structures and absolute configurations of the isolated cannabinoids were confirmed by comparison with the spectroscopic data of the respective compounds obtained by stereoselective synthesis. The butyl homologue of Δ9-THC, Δ9-THCB, showed an affinity for the human CB1 (Ki = 15 nM) and CB2 receptors (Ki = 51 nM) comparable to that of (-)-trans-Δ9-THC. Docking studies suggested the key bonds responsible for THC-like binding affinity for the CB1 receptor. The formalin test in vivo was performed on Δ9-THCB in order to reveal possible analgesic and anti-inflammatory properties. The tetrad test in mice showed a partial agonistic activity of Δ9-THCB toward the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/31891265

https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00876

Antioxidative and Anti-Inflammatory Properties of Cannabidiol.

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antioxidants-logo“Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31881765

https://www.mdpi.com/2076-3921/9/1/21

Medicinal and Synthetic Cannabinoids for Pediatric Patients: A Review of Clinical Effectiveness and Guidelines [Internet].

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Cover of Medicinal and Synthetic Cannabinoids for Pediatric Patients: A Review of Clinical Effectiveness and Guidelines“Cannabinoids are pharmacologically active agents extracted from the cannabis plant. Cannabidiol and tetrahydrocannabinol (THC) are the most studied cannabinoids and both interact with endocannabinoid receptors in various human tissues. The endocannabinoid system moderates physiological functions, such as neurodevelopment, cognition, and motor control.

The products naturally derived from cannabis include marijuana (dried leaves and flowers, mostly for smoking) and oral cannabinoid extracts with varying concentrations of cannabinoids, including cannabidiol and THC. THC is the main psychoactive constituent and cannabidiol seems to have no psychoactive properties. In addition, there are two synthetical cannabinoids approved by the Food and Drug Administration (FDA) in the United States, dronabinol and nabilone, which are molecules similar to a type of THC (δ-9-THC)1 Nabilone is also approved in Canada. Dronabinol is indicated for chemotherapy-induced nausea and vomiting in children. The use of nabilone in children is not recommended.

In Canada, the minimum age for cannabis consumption varies by provinces and territories, and is either 18 or 19 years. A prescription is required to administer cannabinoids among children. Clinically, cannabis has been used to treat children with epilepsy, cancer palliation and primary treatment, chronic pain, and Parkinson disease.

The adverse events that clinicians need to monitor for include negative psychoactive sequelae and development of tolerance. Psychoactive sequelae may be positive, such as relaxation and euphoria, or negative, such as anxiety and irritability. In 2016, CADTH completed a Summary of Abstracts report on the use of cannabis in children with medical conditions such as attention deficit hyperactivity disorder, autism spectrum disorder, Tourette syndrome, epilepsy, posttraumatic stress disorder, or neurodegenerative diseases, and five non-randomized studies were identified. However, there were no control groups in the five studies included in the report.

It is unclear whether there is new evidence or clinical guidance for the use of medical cannabis in children with mental health conditions, neurodegenerative diseases, or pain disorders, particularly in comparison with other possible therapies for those conditions. There is a need to review the clinical effectiveness of cannabis for pediatric care, as well as clinical guidelines.”

https://www.ncbi.nlm.nih.gov/pubmed/31873990

https://www.ncbi.nlm.nih.gov/books/NBK551866/