Category Archives: Endocannabinoid System

Exploiting cannabinoid and vanilloid mechanisms for epilepsy treatment.

Posted on by
Reply

“This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and “transient receptor potential cation channel, subfamily V, member 1” (TRPV1) channel blockers in epilepsy treatment.

The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies.

Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 (“vanilloid”) channel, a possible anandamide target in the brain, have also been investigated.

In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31839498

“Cannabidiol is in clinical use for refractory epilepsies.”

https://www.epilepsybehavior.com/article/S1525-5050(19)30373-7/fulltext

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

Posted on by
Reply

 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z

Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis.

Posted on by
Reply

 Image result for J Gastrointestin Liver Dis“Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy.

Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C.

METHODS:

Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR).

RESULTS:

Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo.

CONCLUSIONS:

The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/31826058

https://www.jgld.ro/jgld/index.php/jgld/article/view/265

Missing Pieces to the Endocannabinoid Puzzle.

Posted on by
Reply

Image result for trends in molecular medicine“The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals.”

https://www.ncbi.nlm.nih.gov/pubmed/31822395

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30293-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS147149141930293X%3Fshowall%3Dtrue

Structure-Effect Relationships of Novel Semi-Synthetic Cannabinoid Derivatives.

Posted on by
Reply

Image result for frontiers in pharmacology“As a library of cannabinoid (CB) derivatives with (-)-trans–cannabidiol (CBD) or (-)-trans-cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), n-hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and n-hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models.

Materials and Methods: Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells. Inhibition of interleukin (IL)-17-induced pro-inflammatory cytokines and chemokines [IL-6, IL-1β, CC-chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α] was studied in RAW264.7 macrophages at the RNA level. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8, and TNF-α) expression and prostaglandin E2 (PGE2) expression were investigated at the protein level in lipopolysaccharide (LPS)-treated primary human monocytes.

Results: Derivatives with long aliphatic side chains at the ester position at R1 [HC (5)] as well as the ones with polar side chains [2-HECBDV (7), NMSC (6), and 2-HEC (1)] can be selective for CB2-receptors. The CBDV-derivatives HCBDV and CHCBDV demonstrated specific binding at CB1- and CB2-receptors at nanomolar concentrations. 2-HEC, 2-HPC, GCBD, and NMSC were agonists at CB2-receptor and antagonists at CB1-receptor. CHC bound both receptors at submicromolar ranges and was an agonist for these receptors. 2-HECBDV was an agonist at CB2-receptor and an antagonist at the CB1-receptor despite its modest affinity at this receptor (micromolar range). NMSC inhibited NF-κB and NFAT activity, and 2-HEC, 2-HPC, and GCBD dose-dependently inhibited PMA/IO-stimulated NFAT activation. CHC and HC dose-dependently reduced IL-1β and CCL2 messenger RNA (mRNA) expression. NMSC inhibited IL-1β, CCL2, and TNF-α at lower doses. At higher doses, it induced a pronounced increase in IL-6 mRNA. 2-HEC, 2-HPC, and GCBD dose-dependently inhibited LPS-induced IL-1β, TNF-α, and IL-6 synthesis. NMSC further increased LPS-stimulated IL-1β release but inhibited IL-8, TNF-α, and PGE2.

Conclusion: The CBD- and CBDV-derivatives studied are suitable for targeting CB-receptors. Some may be used as selective CB2 agonists. The length of the aliphatic rest at R2 of CBD (pentyl) and CBDV (propyl) did not correlate with the binding affinity. Higher polarity at R1 appeared to favor the agonistic activity at CB2-receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/31824305

https://www.frontiersin.org/articles/10.3389/fphar.2019.01284/full

Activation of Cannabinoid Receptors Attenuates Endothelin-1-induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.

Posted on by
Reply

Image result for Journal of Cardiovascular Pharmacology.“Evidence suggests that activation of the endocannabinoid system offers cardioprotection.

Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1).

Acute exposure to ET1 (4 h) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization, and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (i.e. peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase (CPT)-1β, facilitator of fatty acid uptake).

A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of PGC-1α and CPT-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively.

Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multi-factorial problem of cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31815823

https://insights.ovid.com/crossref?an=00005344-900000000-98463

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts.

Posted on by
Reply

Image result for journal of developmental origins of health and disease “The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function.

In pregnancy, LA is vital for foetal development.

Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring’s heart.”

https://www.ncbi.nlm.nih.gov/pubmed/31814560

https://www.cambridge.org/core/journals/journal-of-developmental-origins-of-health-and-disease/article/effect-of-high-maternal-linoleic-acid-on-endocannabinoid-signalling-in-rodent-hearts/C92E2C1126249B7CF9D8A929F0E52FA2

“A number of previous studies have shown that polyunsaturated fatty acids (PUFAs) and phytosterols are critically important for human health. Hempseed is a rich source of plant oil, which contains more than 80% PUFAs. The fatty acids in hempseed oil include a variety of essential fatty acids, including linoleic acid ”

https://link.springer.com/article/10.1007%2Fs10059-011-0042-6

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids.

Posted on by
Reply

ijms-logo“Epilepsy is a neurological disorder that affects approximately 50 million people worldwide.

There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown.

Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies.

We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment.

There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/31810321

https://www.mdpi.com/1422-0067/20/23/6079

The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling.

Posted on by
Reply

 “Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer’s disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear.

WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion.

These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31808139

https://link.springer.com/article/10.1007%2Fs12640-019-00141-8

Cannabinoid receptor 2 promotes the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.

Posted on by
Reply

International Immunopharmacology“High mobility group box 1 (HMGB1) is a late phase inflammatory mediator in many inflammatory diseases. Extracellular HMGB1 could bind to many membrane receptors to activate downstream signaling molecules and promote inflammation resulting in cell and tissue damage.

In our previous work, we found cannabinoid receptor Ⅱ(CB2R) inhibited the expression of HMGB1 in lipopolysaccharide (LPS)-induced septic models in vivo and in vitro, but the underlying mechanism is still unclear.

The present study was aimed to explore the possible pathway through which CB2R suppressed HMGB1.

Here, we found that the specific agonist of CB2R, GW405833 (GW) could induce intracellular HMGB1 degradation without influencing HMGB1 mRNA in peritoneal macrophages. Then we observed that autophagy inhibitor 3-methyladenine (3-MA) but not proteasome inhibitor MG-132 (MG) could block GW-induced HMGB1 degradation, which indicated that the autophagy-lysosome but not the ubiquitination pathway was involved in this process.

Further study showed that GW could promote the integrity of autophagy flux in macrophages in terms of increased level of LC3Ⅱand decreased expression of p62 protein. It also observed that inhibition of autophagy blocked GW-induced nuclear translocation of HMGB1 in macrophages. GW could up-regulate expression of Cathepsin B (CTSB), and inhibition of CTSB blocked GW-induced HMGB1 degradation.

In summary, all the data showed that activation of CB2R could promote the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.”

https://www.ncbi.nlm.nih.gov/pubmed/31806570

https://www.sciencedirect.com/science/article/pii/S1567576919321186?via%3Dihub