Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses.

“The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells.

Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer’s disease and amyotrophic lateral sclerosis.

A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors.

In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25601726

Cannabis use in relation to obesity and insulin resistance in the inuit population.

“OBJECTIVE:

To ascertain the relationship between cannabis use, obesity, and insulin resistance…

Cannabis use was highly prevalent in the study population and was statistically associated with lower body mass index (BMI)

CONCLUSIONS:

Cannabis use was associated with lower BMI, and such an association did not occur through the glucose metabolic process or related inflammatory markers. The association between cannabis use and insulin resistance was mediated through its influence on weight.”

http://www.ncbi.nlm.nih.gov/pubmed/25557382

Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of Cerebral Malaria.

Neuroscience

“Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparuminfection that might cause permanent neurological deficits.

Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties.

In the present work, we evaluated the effects of CBD in a murine model of CM.

CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6).

Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.”

http://www.ncbi.nlm.nih.gov/pubmed/25595981

“Cannabidiol adjuvant treatment increases survival in the murine model of CM. Cannabidiol adjuvant treatment promotes rescue of behavioral and cognitive function.”

https://www.sciencedirect.com/science/article/pii/S0306452215000196

http://www.thctotalhealthcare.com/category/malaria/

Selective CB2 receptor agonists.

“Selective CB2 receptor agonists. Part 1: The identification of novel ligands through computer-aided drug design (CADD) approaches. Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.”  http://www.ncbi.nlm.nih.gov/pubmed/25556098

“Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds. Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.” http://www.ncbi.nlm.nih.gov/pubmed/25556092

“Selective CB2 receptor agonists. Part 3: The optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model. A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.” http://www.ncbi.nlm.nih.gov/pubmed/25575658

 

Beneficial effects of cannabinoid receptor type 2 (CB2R) in injured skeletal muscle post-contusion.

“The aim of the current study was to investigate the effects of cannabinoid receptor type 2 (CB2R) on the repair process of injured skeletal muscle, which could potentially lay solid foundations as a novel target for curing muscular fibrosis in future…

These results revealed multiple effects of CB2R in systematically inhibiting fibrotic formation and improving muscle regeneration, alongside its potential for clinical application in patients with skeletal muscle injuries and diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/25588471

Cannabinoid CB1 receptors in the dorsal hippocampus and prelimbic medial prefrontal cortex modulate anxiety-like behavior in rats: additional evidence.

“Endocannabinoids (ECBs) such as anandamide (AEA) act by activating cannabinoid type 1 (CB1) or 2 (CB2) receptors. The anxiolytic effect of drugs that facilitate ECB effects is associated with increase in AEA levels in several encephalic areas, including the prefrontal cortex (PFC).

Activation of CB1 receptors by CB1 agonists injected directly into these areas is usually anxiolytic.

However, depending on the encephalic region being investigated and on the stressful experiences, opposite effects were observed, as reported in the ventral HIP. In addition, contradictory results have been reported after CB1 activation in the dorsal HIP (dHIP).

Therefore, in the present paper we have attempted to verify if directly interfering with ECB metabolism/reuptake in the prelimbic (PL) portion of the medial PFC (MPFC) and dHIP would produce different effects in two conceptually distinct animal models: the elevated plus maze (EPM) and the Vogel conflict test (VCT).

We observed drugs which interfere with ECB reuptake/metabolism in both the PL and in the dentate gyrus of the dHIP induced anxiolytic-like effect, in both the EPM and in the VCT via CB1 receptors, suggesting CB1 signaling in these brain regions modulate defensive responses to both innate and learned threatening stimuli.

This data further strengthens previous results indicating modulation of hippocampal and MPFC activity via CB1 by ECBs, which could be therapeutically targeted to treat anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25595265

http://www.thctotalhealthcare.com/category/anxiety-2/

Two non-psychoactive cannabinoids reduce intra-cellular lipid levels and inhibit hepatosteatosis.

“Obesity and associated metabolic syndrome have quickly become a pandemic and a major detriment to human health globally.

The presence of non-alcoholic fatty liver disease (NAFLD; hepatosteatosis) in obesity has been linked to the worsening of the metabolic syndrome, including the development of insulin resistance and cardiovascular disease. Currently, there are few options to treat NAFLD, including life style changes and insulin sensitizers.

Recent evidence suggests that the cannabinoids Δ9-tetrahydrocannabivarin (THCV) and cannabidiol (CBD) improve insulin sensitivity; we aimed at studying their effects on lipid levels…

THCV and CBD directly reduce accumulated lipid levels in vitro in a hepatosteatosis model and adipocytes.

…these cannabinoids are able to increase yolk lipid mobilization and inhibit the development of hepatosteatosis respectively.

CONCLUSIONS:

Our results suggest that THCV and CBD might be used as new therapeutic agents for the pharmacological treatment of obesity- and metabolic syndrome-related NAFLD/hepatosteatosis.”

http://www.ncbi.nlm.nih.gov/pubmed/25595882

http://www.thctotalhealthcare.com/category/obesity-2/

Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension.

“Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways…

Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension…

Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice.

These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation.

Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone.

Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.”

http://www.ncbi.nlm.nih.gov/pubmed/25595485

http://www.thctotalhealthcare.com/category/hypertension-high-blood-pressure/

Medical marijuana for cancer.

“Marijuana has been used for centuries, and interest in its medicinal properties has been increasing in recent years. Investigations into these medicinal properties has led to the development of cannabinoid pharmaceuticals such as dronabinol, nabilone, and nabiximols.

Dronabinol is best studied in the treatment of nausea secondary to cancer chemotherapy and anorexia associated with weight loss in patients with acquired immune deficiency syndrome, and is approved by the US Food and Drug Administration for those indications.

Nabilone has been best studied for the treatment of nausea secondary to cancer chemotherapy. There are also limited studies of these drugs for other conditions.

Nabiximols is only available in the United States through clinical trials, but is used in Canada and the United Kingdom for the treatment of spasticity secondary to multiple sclerosis and pain.

Studies of marijuana have concentrated on nausea, appetite, and pain.

This article will review the literature regarding the medical use of marijuana and these cannabinoid pharmaceuticals (with emphasis on indications relevant to oncology)”

http://www.ncbi.nlm.nih.gov/pubmed/25503438

“Both cannabis and cannabinoid pharmaceuticals can be helpful for a number of problems, including many affecting patients with cancer… given the limitations inherent in using oral medications to treat nausea and vomiting, inhalation of marijuana or a cannabinoid may be better than oral ingestion in treating this condition.” http://onlinelibrary.wiley.com/doi/10.3322/caac.21260/full

http://www.thctotalhealthcare.com/category/cancer/

Association Between Marijuana Exposure and Pulmonary Function over 20 Years

TU Dublin Kevin St Library: New: American Medical Association journals (JAMA)  collection now available via IReL“Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.

Marijuana may have beneficial effects on pain control, appetite, mood, and management of other chronic symptoms.

Our findings suggest that occasional use of marijuana for these or other purposes may not be associated with adverse consequences on pulmonary function.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840897/

https://jamanetwork.com/journals/jama/fullarticle/1104848

“A common misconception about medical marijuana is that if inhaled, it will have detrimental effects on the patient’s lungs. However, according to a 2012 study published in the Journal of the American Medical Association (JAMA), this notion is simply untrue; in fact, this study points to an idea quite the opposite: that medical marijuana just might improve lung health under certain conditions.” HTTPS://AGRIMEDINDUSTRIES.COM/2018/06/08/STUDY-SHOWS-MARIJUANA-HAS-A-POSITIVE-IMPACT-ON-LUNG-HEALTH-UNDER-CERTAIN-CONDITIONS/