The multiplicity of action of cannabinoids: implications for treating neurodegeneration.

“The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the G-protein coupled CB receptors, CB(1) and CB(2).

These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands.

The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis.

Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration.

Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer’s disease, multiple sclerosis, and cerebral ischemia.

This article will discuss the experimental and clinical evidence supporting a potential role for CB-based therapies in the treatment of certain neurological diseases that feature a neurodegenerative component.”

http://www.ncbi.nlm.nih.gov/pubmed/20875047

Cannabinoid WIN‑55,212‑2 mesylate inhibits ADAMTS‑4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan‑1.

“A central feature of osteoarthritis (OA) is the loss of articular cartilage, which is primarily attributed to cartilage breakdown.

Accumulating evidence also suggests that cannabinoids have chondroprotective effects.

In conclusion, to the best of our knowledge, the present study provides the first in vitro evidence supporting that the synthetic cannabinoid WIN‑55 inhibits ADAMTS‑4 activity in unstimulated and IL‑1β‑stimulated human OA articular chondrocytes by decreasing the mRNA stability/expression of syndecan‑1 via CB2.

This suggests a novel mechanism by which cannabinoids may prevent cartilage breakdown in OA.

In addition, it also provides novel insights into the pharmacological effects of synthetic cannabinoids on OA.” http://www.ncbi.nlm.nih.gov/pubmed/27082728

“Chondroprotective: A specific compound or chemical that delays progressive joint space narrowing characteristic of arthritis and improvesthe biomechanics of articular joints by protecting chondrocytes.”   http://medical-dictionary.thefreedictionary.com/chondroprotective

An update on peroxisome proliferator-activated receptor (PPAR) activation by cannabinoids.

“Some cannabinoids activate the different isoforms of peroxisome proliferator-activated receptors (PPARs; α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies.

Activation of all isoforms, but primarily PPARα and γ, mediate some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumoral, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as CB1 , CB2 and TRPV1.

PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins (FABPs).

The aim of this review is to update the evidence supporting PPAR activation by cannabinoids, and review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.”

http://www.ncbi.nlm.nih.gov/pubmed/27077495

Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.

“Toll-like receptors (TLRs) are the sensors of pathogen-associated molecules that trigger tailored innate immune intracellular signalling responses to initiate innate immune reactions.

Data from the experimental autoimmune encephalomyelitis (EAE) model indicates that TLR signalling machinery is a pivotal player in the development of murine EAE. To compound this, data from human studies indicate that complex interplay exists between TLR signalling and Multiple Sclerosis (MS) pathogenesis.

Cannabis-based therapies are in clinical development for the management of a variety of medical conditions, including MS. In particular Sativex®, a combination of plant-derived cannabinoids, is an oromucosal spray with efficacy in MS patients, particularly those with neuropathic pain and spasticity.

Despite this, the precise cellular and molecular mechanisms of action of Sativex® in MS patients remains unclear. This review will highlight evidence that novel interplay exists between the TLR and cannabinoid systems, both centrally and peripherally, with relevance to the pathogenesis of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/27079840

Synthesis and pharmacological evaluation of new biphenylic derivatives as CB2 receptor ligands.

“Targeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer.

Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor.

In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4′ and 5 of the biphenyl scaffold.

Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4′, with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists.

This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays.”

http://www.ncbi.nlm.nih.gov/pubmed/27078864

Polyphenolic Compounds and Antioxidant Activity of Cold-Pressed Seed Oil from Finola Cultivar of Cannabis sativa L.

“The aim of this study was to characterize the polyphenolic compounds and antioxidant activity of cold-pressed seed oil from Finola cultivar of industrial hemp (Cannabis sativa L.).

Several methodologies have been employed to evaluate the in vitro antioxidant activity of Finola hempseed oil (FHSO) and both lipophilic (LF) and hydrophilic fractions (HF). The qualitative and quantitative composition of the phenolic fraction of FHSO was performed by HPLC analyses.

From the results is evident that FHSO has high antioxidative activity, as measured by DPPH radical (146.76 mmol of TE/100 g oil), inhibited β-carotene bleaching, quenched a chemically generated peroxyl radical in vitro and showed high ferrous ion chelating activity. Reactivity towards 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical cation and ferric-reducing antioxidant power values were 695.2 µmol of TE/100g oil and 3690.6 µmol of TE/100 g oil respectively.

FHSO contains a significant amount of phenolic compounds of which 2780.4 mg of quercetin equivalent/100 g of total flavonoids.

The whole oil showed higher antioxidant activity compared with LF and HF.

Our findings indicate that the significant antioxidant properties shown from Finola seed oil might generally depend on the phenolic compounds, especially flavonoids, such as flavanones, flavonols, flavanols and isoflavones.”

http://www.ncbi.nlm.nih.gov/pubmed/27076277

Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed type hypersensitivity.

“Endocannabinoids are endogenous ligands for the cannabinoid (CB) receptors which include anandamide (AEA) and (2-AG). 2-AG has been linked to inflammation due to its elevated expression in animal models of autoimmunity and hypersensitivity.

However, administration of exogenous 2-AG has been shown to suppress inflammation making its precise role unclear. In the current study, we investigated the role of 2-AG following immunization of C57BL/6 (BL6) mice with methylated BSA (mBSA) antigen, which triggers both delayed type hypersensitivity (DTH) and antibody response.

Together, these data show for the first time that activated T and B cells produce 2-AG, which plays a negative regulatory role to decrease DTH via inhibition of T-cell activation and proliferation.

Moreover, these findings suggest that exogenous 2-AG treatment can be used therapeutically in Th1- or Th17-driven disease.”  http://www.ncbi.nlm.nih.gov/pubmed/27064137

“∆9-Tetrahydrocannabinol (THC) is one of the major bioactive cannabinoids derived from the Cannabis sativa plant and is known for its anti-inflammatory properties. Delayed-type hypersensitivity (DTH) is driven by proinflammatory T helper cells including the classic inflammatory Th1 lineage as well as the more recently discovered Th17 lineage. In the current study, we investigated whether THC can alter the induction of Th1/Th17 cells involved in mBSA-induced DTH response… In summary, the current study suggests that THC treatment during DTH response can simultaneously inhibit Th1/Th17 activation via regulation of microRNA (miRNA) expression.• THC treatment inhibits simultaneous Th1/Th17 driven inflammation. • THC treatment corrects DTH-mediated microRNA dysregulation. • THC treatment regulates proinflammatory cytokines and transcription factors.” http://www.ncbi.nlm.nih.gov/pubmed/27038180

No significant effect of cannabis use on the count and percentage of circulating CD4 T-cells in HIV-HCV co-infected patients (ANRS CO13-HEPAVIH French cohort).

“Despite cannabis use being very common in patients co-infected with HIV and hepatitis C virus (HCV), its effect on these patients’ immune systems remains undocumented.

Documenting the potential effect of cannabis use on HIV immunological markers would help caregivers make more targeted health recommendations to co-infected patients.

We performed a longitudinal analysis of the relationship betweencannabis use and peripheral blood CD4 T-cell measures in co-infected patients receiving antiretroviral therapy.

Findings show no evidence for a negative effect of cannabis use on circulating CD4 T-cell counts/percentages in HIV-HCV co-infected patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27073179

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

Cannabidiol promotes browning in 3T3-L1 adipocytes.

“Recruitment of the brown-like phenotype in white adipocytes (browning) and activation of existing brown adipocytes are currently being investigated as a means to combat obesity.

The present study was designed to investigate the effects of cannabidiol (CBD), a major nonpsychotropic phytocannabinoid of Cannabis sativa, on induction of browning in 3T3-L1 adipocytes.

These data suggest possible roles for CBD in browning of white adipocytes, augmentation of lipolysis, thermogenesis, and reduction of lipogenesis.

In conclusion, the current data suggest that CBD plays dual modulatory roles in the form of inducing the brown-like phenotype as well as promoting lipid metabolism.

Thus, CBD may be explored as a potentially promising therapeutic agent for the prevention of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/27067870

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

Antitumorigenic targets of cannabinoids – current status and implications.

“Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment.

The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids.

Expert opinion: The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds.

In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions.

Thus, drugs aiming at the endocannabinoid system may represent potential “antimetastatics” for an upgrade of a future armamentarium against cancer diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27070944

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