Δ9-Tetrahydrocannabinol suppresses monocyte-mediated astrocyte production of MCP-1 and IL-6 in a TLR7-stimulated human co-culture.

Journal of Pharmacology and Experimental Therapeutics“Cannabis is widely used in the United States with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, in particular, Δ9-tetrahydrocannabinol (THC), possess immune modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial, such as in treating inflammatory diseases, or detrimental to normal immune defense against pathogens. The potential beneficial impact of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., HIV-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human co-culture system, monocyte-derived IL-1β due to toll-like receptor 7 (TLR7)-activation, has been identified to promote astrocyte production of MCP-1 and IL-6. THC treatment of TLR7-stimulated co-culture suppressed monocyte secretion of IL-1β resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1β production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1β production similar to that of THC, suggesting THC is, in part, acting through CB2. THC also suppressed key elements of the IL-1β production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1β, through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6.

SIGNIFICANCE STATEMENT: As cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human co-culture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC) and a cannabinoid receptor-2 (CB2) selective agonist, suppress specific monocyte-mediated astrocyte inflammatory responses. In the context of viral-induced chronic neuroinflammation, the findings presented here suggest that cannabinoids via CB2 ligation may have beneficial anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31383729

http://jpet.aspetjournals.org/content/early/2019/08/05/jpet.119.260661

Cannabis and Epilepsy.

 Publication Cover“In recent years, the use of cannabidiol in the treatment of refractory epilepsy has been increasingly investigated and has been gaining public support as a novel way to treat these disorders.

Marijuana has been used for medical purposes for thousands of years, and a lot of research has been conducted over the last several decades into the chemistry and pharmacology of marijuana and its many compounds, including cannabidiol.

There are historical and recent scientific developments that support the use of cannabidiol in rare severe epilepsy syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/31385740

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1645372?journalCode=wjdd20

Cannabidiol Regulates the Expression of Keratinocyte Proteins Involved in the Inflammation Process through Transcriptional Regulation.

cells-logo “Cannabidiol (CBD), a natural phytocannabinoid without psychoactive effect, is a well-known anti-inflammatory and antioxidant compound.

The possibility of its use in cytoprotection of cells from harmful factors, including ultraviolet (UV) radiation, is an area of ongoing investigation. Therefore, the aim of this study was to evaluate the effect of CBD on the regulatory mechanisms associated with the redox balance and inflammation in keratinocytes irradiated with UVA [30 J/cm2] and UVB [60 mJ/cm2].

Spectrophotometric results show that CBD significantly enhances the activity of antioxidant enzymes such as superoxide dismutase and thioredoxin reductase in UV irradiated keratinocytes. Furthermore, despite decreased glutathione peroxidase and reductase activities, CBD prevents lipid peroxidation, which was observed as a decreased level of 4-HNE and 15d-PGJ2 (measured using GC/MS and LC/MS). Moreover, Western blot analysis of protein levels shows that, under stress conditions, CBD influences interactions of transcription factors Nrf2- NFκB by inhibiting the NFκB pathway, increasing the expression of Nrf2 activators and stimulating the transcription activity of Nrf2.

In conclusion, the antioxidant activity of CBD through Nrf2 activation as well as its anti-inflammatory properties as an inhibitor of NFκB should be considered during design of new protective treatments for the skin.”

https://www.ncbi.nlm.nih.gov/pubmed/31382646

https://www.mdpi.com/2073-4409/8/8/827

Endogenous cannabinoid levels and suicidality in combat veterans.

Psychiatry Research“Combat veterans are at elevated suicide risk. The goal of this study was to test the hypothesis that combat veterans who have made a suicide attempt post-deployment can be distinguished from combat veterans who have never made a suicide attempt based on differences in psychological and biological variables. For the latter, we focused on endogenous cannabinoids, neuroendocrine markers that are associated with stress. Demographic and clinical parameters of suicide attempters and non-attempters were assessed. Blood samples were assayed for anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cortisol. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores in comparison to non-attempters. Controlling for gender, 2-AG levels were higher among suicide attempters in comparison to non-attempters. Cortisol levels positively correlated with 2-AG levels and negatively correlated with SSI scores among non-attempters but not among attempters. AEA levels negatively correlated with SSI scores among attempters but not among non-attempters. Our results indicate that there are psychological and biological differences between combat veterans with or without a history of suicidal attempt. Our findings also suggest that clinically observed differences between the groups may have a neurobiological basis.”

https://www.ncbi.nlm.nih.gov/pubmed/31375282

https://www.sciencedirect.com/science/article/abs/pii/S0165178119315173?via%3Dihub

“Role of the Endocannabinoid System in the Neurobiology of Suicide”  https://www.ncbi.nlm.nih.gov/books/NBK107200/

Intraperitoneal cannabidiol attenuates neonatal germinal matrix hemorrhage-induced neuroinflamtion and perilesional apoptosis.

Publication Cover“As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage.

Results. Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the Stratum oriens of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol.

Conclusion. The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.”

Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.

 “Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties.

During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy.

In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal.

In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS.

Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex.

The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances.

About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.”

https://www.ncbi.nlm.nih.gov/pubmed/31372958

https://link.springer.com/article/10.1007%2Fs40265-019-01171-4

A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome.

 

Image result for journal of neurodevelopmental disorders“Fragile X syndrome (FXS) is characterized by a range of developmental, neuropsychiatric, and behavioral symptoms that cause significant impairment in those with the disorder.

Cannabidiol (CBD) holds promise as a potential treatment for FXS symptoms due to its safety profile and positive effects on a number of emotional and behavioral symptoms associated with FXS.

The aim of the current study was to evaluate the safety, tolerability, and initial efficacy of ZYN002, a transdermal CBD gel, in a pediatric population with FXS.

RESULTS:

The majority of treatment-emergent AEs (reported by 85% of participants) were mild in severity (70%), and no serious adverse events were reported. There was a statistically significant reduction in ADAMS total score from screening to week 12 and significant reductions on nearly all other secondary endpoints, including all ADAMS subscales (except depressed mood), all ABC-CFXS subscale scores (e.g., social avoidance, irritability), PARS-R total severity score, and PedsQL total score.

CONCLUSIONS:

ZYN002 was well tolerated and produced clinically meaningful reductions in anxiety and behavioral symptoms in children and adolescents with FXS. These findings support further study of ZYN002 in a randomized, well-controlled trial for the treatment of behavioral symptoms of FXS.”

https://www.ncbi.nlm.nih.gov/pubmed/31370779

https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-019-9277-x

β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR-γ Receptors.

biomolecules-logo “β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation.

An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) has been suggested and PPAR-γ activation exerts anti-arthritic effects.

The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR-γ involvement in a collagen antibody induced arthritis (CAIA) experimental model.

BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13. BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR-γ. These conditions were reverted following BCP treatment.

Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR-γ expression in human articular chondrocytes stimulated with LPS. These effects were reverted by AM630, a CB2 receptor antagonist.

These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.”

https://www.ncbi.nlm.nih.gov/pubmed/31370242

https://www.mdpi.com/2218-273X/9/8/326

“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

The curative effect of cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion.

Fundamental &amp; Clinical Pharmacology banner“Ischemia and reperfusion of intestinal tissue (intestinal I/R) induces disruption of ileal contractility and chain responses of inflammatory.

The aim of this study was to reveal whether therapeutic value of cannabinoid 2 (CB2) receptor activity in the intestinal I/R, via to the exogenous administration of CB2 agonist (AM-1241).

Intestinal I/R injury were performed through 30 min ischemia and 150 min reperfusion of mesenteric artery in Wistar rats. The pre-administered doses of 0.1, 1, and 5 mg/kg of CB2 agonist were studied to inhibit inflammation of intestinal I/R injury including ileum smooth muscle contractility, polymorphonuclear cell migration, oxidant/antioxidant defence system, and provocative cytokines.

Pre-administration with CB2 receptor agonist ensured to considerable improving the disrupted contractile responses in ileum smooth muscle along with decreased the formation of MDA that production of lipid peroxidation, reversed the depleted glutathione, inhibited the expression of TNF-α and of IL-1β in the intestinal I/R of rats.

Taken together results of this research, the agonistic activity of CB2 receptor for healing of intestinal I/R injury is ensuring associated with anti-inflammatory mechanisms such as the inhibiting of migration of inflammatory polymorphonuclear cells that origin of acute and initial responses of inflammation, the inhibiting of production of provocative and pro-inflammatory cytokines like TNF-α and IL-1β, the rebalancing of oxidant/antioxidant redox system disrupted in injury of reperfusion period, and the supporting of physiologic defensive systems in endothelial and inducible inflammatory cells.”

https://www.ncbi.nlm.nih.gov/pubmed/31373049

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12502

Cannabichromene is a cannabinoid CB2 receptor agonist.

British Journal of Pharmacology banner“Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 – tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.

KEY RESULTS:

CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.

CONCLUSIONS AND IMPLICATIONS:

CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31368508

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14815