Cannabinoids, inflammation, and fibrosis.

Posted on November 3, 2016 by David

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“Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).

As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis.

A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ⁹-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented.

The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed.

The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances.

Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents.

Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.”

https://www.ncbi.nlm.nih.gov/pubmed/27435265

Cannabinoid Receptor 2 Activation Restricts Fibrosis and Alleviates Hydrocephalus after Intraventricular Hemorrhage.

Posted on October 23, 2016 by David

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“Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH).

The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases.

However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model.

In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1.”

https://www.ncbi.nlm.nih.gov/pubmed/27769788

Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy.

Posted on August 30, 2016 by David

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“Proliferative vitreoretinopathy (PVR) can develop after ocular trauma or inflammation and is a common complication of surgery to correct retinal detachment.

Currently, there are no pharmacological treatments for PVR.

Cannabinoids acting at cannabinoid 2 receptor (CB2R) can decrease inflammation and fibrosis.

The objective of this study was to examine the anti-inflammatory actions of CB2R as a candidate novel therapeutic target in experimental PVR.

In conclusion, our results indicate that intervention at early stage PVR with CB2R agonists reduces ocular inflammation and disease severity.

CB2R may represent a therapeutic target to prevent PVR progression and vision loss.”

http://www.ncbi.nlm.nih.gov/pubmed/27569993

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy

Posted on July 18, 2016 by David

“CBD, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts antiinflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans.

In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrosative stress, cell death and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose.

A previous study has demonstrated cardiac protection by CBD in myocardial ischemic reperfusion injury; therefore, we have investigated the potential protective effects of CBD in diabetic hearts and in primary human cardiomyocytes exposed to high glucose.

Our findings underscore the potential of CBD for the prevention/treatment of diabetic complications.

Collectively, these results coupled with the excellent safety and tolerability profile of cannabidiol in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrosative stress, inflammation, cell death and fibrosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026637/

Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts.

Posted on May 28, 2016 by David

Rheumatology

“Recently, it has also been demonstrated that the pleiotropic cannabinoid system is involved in both liver and pancreatic fibrosis. Furthermore, cannabinoids may play a pro- or anti-fibrogenic role depending on their interaction with CB1r or CB2r.

This raises the possibility that pharmacologic modulation of the endocannabinoid system could be a target to limit tissue damage in pathologic fibrosis.

It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis.

Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls.

Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.”

http://rheumatology.oxfordjournals.org/content/48/9/1050.long

Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.

Posted on March 12, 2016 by David

“Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl₄-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl₄-induced cannabinoid receptor 1 (CB₁ receptor) expression and increased cannabinoidreceptor 2 (CB₂ receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/26945822

The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

Posted on February 19, 2016 by David

“Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs.

Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis.

Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies.

We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity.

The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630.

In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26887982

Cannabinoids and autoimmune diseases: A systematic review.

Posted on February 17, 2016 by David

“Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release.

Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines.

In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus.

They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma.

Studies in human models are scarce and not conclusive and more research is required in this field.

Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26876387

http://www.thctotalhealthcare.com/category/autoimmune-disease/

Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1.

Posted on October 2, 2015 by David

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“Radiation-induced pulmonary fibrosis (RIF) is a severe complication of thoracic radiotherapy that limits its dose, intensity, and duration. The contribution of the endocannabinoid signaling system in pulmonary fibrogenesis is not known. Using a well-established mouse model of RIF, we assessed the involvement of cannabinoid receptor-1 (CB1) in the onset and progression of pulmonary fibrosis.

Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation.”

http://www.ncbi.nlm.nih.gov/pubmed/26426981

“We report for the first time the involvement of cannabinoid receptor 1 (CB₁)-mediated signaling in the onset and progression of radiation-induced pulmonary fibrosis (RIF). We were able to delay the onset of RIF by genetic targeting of CB₁ receptors as well as by its pharmacological inhibition. Thus, pharmacological targeting of CB₁ receptors with peripherally restricted CB₁ antagonists void of central nervous system complications may represent a novel strategy to prevent the development of RIF.

In summary, we provide the first evidence on the key pathological role of CB₁ signaling in radiation-induced pulmonary fibrogenesis and show that peripherally restricted CB₁ antagonists may represent a novel therapeutic approach against this devastating and untreatable complication of radiotherapy/irradiation. Our results also suggest that targeting CB₁ may provide benefits in other lung diseases associated with inflammation and fibrosis.”

http://www.atsjournals.org/doi/10.1165/rcmb.2014-0331OC

CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia.

Posted on June 21, 2015 by David

“Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis-2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy.

Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling…

CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts.

Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy.”

http://www.ncbi.nlm.nih.gov/pubmed/26093151