Monthly Archives: January 2017

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type-2 Diabetes.

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“Islet inflammation promotes β-cell loss and type-2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets.

Here, we analyzed CB1R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates.

Adoptive transfer of CB1R-/- bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy. ZDF islets contain elevated levels of CB1R, IL-1β, TNF-α, the chemokine CCL2 and interferon regulatory factor-5 (IRF5), a marker of M1 inflammatory macrophage polarization.

In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα-dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia.

Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/28082458

Influence of history of cannabis smoking in selected donors on the outcomes of lung transplantation.

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“Cannabis is the most commonly abused illicit drug and the smokers are at the risk of lung infections, bullous emphysema and lung cancer. However, no evidence about the outcomes of lung transplantation (LTx) utilizing the lungs from such donors is available in the literature.

The history of donor cannabis smoking does not appear to affect early and mid-term outcomes after LTx and potentially improve the donor pool. As it does not seem to negatively affect the outcomes after LTx, it should not be per se considered a contraindication for lung donation.”

https://www.ncbi.nlm.nih.gov/pubmed/28077504

“Transplantation is one critical area of medicine that requires the use of immunosuppressants. Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties. Cannabinoids are the tetrophenolic compounds found in the plant, Cannabis sativa.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923447/

Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review.

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“Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear.

RESULTS:

Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression.

CONCLUSIONS:

Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28079617

“Plant cannabinoids THC and CBD proved beneficial in DNBS-induced colitis in a bell-shaped dose-related response, but more importantly, the effects of the phytocannabinoids were additive, as CBD increased an ineffective THC dose to the level of an effective one.” https://academic.oup.com/ibdjournal/article/23/2/192/4347176

Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

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“Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/25504799

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis.

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“Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotrophic lateral sclerosis (ALS).

The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1G93A mutant mice.

Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1).

In summary, our results demonstrated a marked up-regulation of CB2 receptors occurring in the spinal cord in canine DM, which was concentrated in activated astrocytes.

Such receptors may be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.”

https://www.ncbi.nlm.nih.gov/pubmed/28069688

Brain cannabinoid receptor 2: expression, function and modulation.

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“Cannabis sativa (marijuana) is a fibrous flowering plant that produces an abundant variety of molecules, some with psychoactive effects. At least 4% of the world’s adult population uses cannabis annually, making it one of the most frequently used illicit drugs in the world. The psychoactive effects of cannabis are mediated primarily through cannabinoid receptor (CBR) subtypes. The prevailing view is that CB1Rs are mainly expressed in the central neurons, whereas CB2Rs are predominantly expressed in peripheral immune cells. However, this traditional view has been challenged by emerging strong evidence that shows CB2Rs are moderately expressed and function in specific brain areas. New evidence has demonstrated that brain CB2Rs modulate animal drug-seeking behaviors, suggesting that these receptors may exist in brain regions that regulate drug addiction. Recently, we further confirmed that functional CB2Rs are expressed in mouse ventral tegmental area (VTA) dopamine (DA) neurons and that the activation of VTA CB2Rs reduces neuronal excitability and cocaine-seeking behavior. In addition, CB2R-mediated modulation of hippocampal CA3 neuronal excitability and network synchronization has been reported. Here, we briefly summarize recent lines of evidence showing how CB2Rs modulate function and pathophysiology in the CNS.”

https://www.ncbi.nlm.nih.gov/pubmed/28065934

Development of new inhibitors for N-acylethanolamine-hydrolyzing acid amidase as promising tool against bladder cancer.

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“The endocannabinoid system is a signaling system involved in a wide range of biological effects.

Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits.

Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control.

Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines.

These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition.

Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/28062195

Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection.

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“Recent evidence shows that the endocannabinoid system is involved in the pathogenesis of numerous neurodegenerative diseases of the central nervous system. Pharmacologic modulation of cannabinoid receptors or the enzymes involved in the synthesis, transport, or breakdown of endogenous cannabinoids has proved to be a valid alternative to conventional treatment of these diseases.

In this review, we will examine recent findings that demonstrate the involvement of the endocannabinoid system in glaucoma, a major neurodegenerative disease of the eye that is a frequent cause of blindness.

Experimental findings indicate that the endocannabinoid system contributes to the control of intraocular pressure (IOP), by modulating both production and drainage of aqueous humor.

There is also a growing body of evidence of the involvement of this system in mechanisms leading to the death of retinal ganglion cells, which is the end result of glaucoma.

Molecules capable of interfering with the ocular endocannabinoid system could offer valid alternatives to the treatment of this disease, based not only on the reduction of IOP but also on neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/18929127

[Possibilities of applying cannabinoids’ in the treatment of glaucoma].

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“Over a period of several decades numerous scientific research has proven that, regardless of the route of administration, cannabinoids are able to decrease intraocular pressure.

What is more, these compounds are characterized by neuroprotection and vasodilatation properties, that additionally substantiate it’s therapeutic utility in conservative treatment of glaucoma.

So far, it has not been described in details what mechanism is used to lower the intraocular pressure by cannabinoids. Nevertheless, the presence of endocannabinoid receptors in structures of the eye responsible for formation and outflow of aqueous humor is an explanation for effectiveness of these compounds, when administered in topical form.

These days, with the aid of modern pharmacological technology are available significantly bigger possibilities of improving bioavailability of cannabinoids administered to the eye than in the past, as well as limitation of it’s undesired side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/19112869

Soft cannabinoid analogues as potential anti-glaucoma agents.

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“Cannabinoids have intraocular pressure (IOP) lowering effects, thus, they have a therapeutic potential in the treatment of glaucoma.

Our aim was to develop a safer, cannabinoid type anti-glaucoma agent, a topically applied soft analogue, that has local, but no systemic effect.

The lead compound chosen was a nitrogen-containing cannabinoid analogue that was shown to have IOP lowering activity.

A full library of possible soft drugs was generated and the structures were ranked based on the closeness of calculated properties to those of the lead compound.

The lead compound has been synthesized, and a preliminary pharmacological study was performed.

The structure-activity relationship and pharmacological results indicate a good possibility for the development of a safe, soft anti-glaucoma agent.”

https://www.ncbi.nlm.nih.gov/pubmed/10756540