Tag Archives: therapeutic

Endocannabinoids in the gut.

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“The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/27538961

Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson’s Disease.

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“The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson’s disease (PD).

The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD.

In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD.

Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial effects of BCP.

The present study suggests that BCP has the potential therapeutic efficacy to elicit significant neuroprotection by its anti-inflammatory and antioxidant activities mediated by activation of the CB2 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27531971

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis.

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“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis.

CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

For multifactorial chronic diseases, such as fibrosis, the conventional pharmacological approach based on the “one-disease/one-target/one-drug” paradigm limits therapeutic efficacy and could be improved by simultaneously hitting multiple therapeutic targets.

One such target is the endocannabinoid/cannabinoid-1 receptor (endocannabinoid/CB1R) system.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases .

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979564/

Sex-dependent effects of cannabis-induced analgesia.

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“Preclinical studies demonstrate that cannabinoid-mediated antinociceptive effects vary according to sex; it is unknown if these findings extend to humans.

These results indicate that in cannabis smokers, men exhibit greater cannabis-induced analgesia relative to women.

As such, sex-dependent differences in cannabis’s analgesic effects are an important consideration that warrants further investigation when considering the potential therapeutic effects of cannabinoids for pain relief.”

http://www.ncbi.nlm.nih.gov/pubmed/27522535

CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a.

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“The CB1 cannabinoid receptor is a G-protein coupled receptor that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection.

We report the discovery of two structurally related CB1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB1. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans, and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b seems to be unique to primates.

CRIP1a coimmunoprecipitates with CB1receptors derived from rat brain homogenates, indicating that CRIP1a and CB1 interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB1-mediated tonic inhibition of voltage-gated Ca2+ channels.

Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB1 activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).”

http://www.ncbi.nlm.nih.gov/pubmed/17895407

Cannabidiol-2′,6′-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro.

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“15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis.

We have recently reported that cannabidiol-2′,6′-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation.

The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway.

These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.

In sum, these findings suggest that CBDD may be a useful adjuvant in the treatment of atherosclerosis as well as an experimental tool for analyzing the mechanistic details of PUFAs oxygenation by 15-LOX.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012644/

“Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.”  http://www.ncbi.nlm.nih.gov/pubmed/19406952

[Cannabinoids in multiple sclerosis — therapeutically reasonable?].

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“For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies.

Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS.

Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS.

Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms.

Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties.

This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/16052440

Medical Marijuana-Opportunities and Challenges

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“Over the recent years, public and political opinions have demonstrated increasing support for the legalization of medical marijuana.

To date, 24 states as well as the District of Columbia have legalized cannabis for medical use, 4 states have legalized the recreational use of Marijuana.

Marijuana is derived from the hemp plant Cannabis sativa. Δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis, while cannabidiol (CBD) is the major non-psychoactive constituent. THC is a partial agonist at CB1 and CB2 receptors, while CBD at high levels is an antagonist CB1 and CB2.

CB1 is abundantly expressed in the brain, and CB2 is expressed on immune cells (expression of CB2 on neurons remains controversial). The brain also produces endogenous cannabis-like substances (endocannabinoids) that bind and activate the CB1/CB2 receptors.

There is tremendous interest in harnessing the therapeutic potential of plant-derived and synthetic cannabinoids.

This Editorial provides an overview of diseases that may be treated by cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948749/

Effective treatment of spasticity using dronabinol in pediatric palliative care.

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“Cannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far.

We conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care.

Sixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored.

RESULTS:

Drops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (n = 12). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0 mg/kg/d with a median of 0.33 mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each).

No serious and enduring side effects occurred even in young children and/or over a longer period of time.

CONCLUSIONS:

In the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity.”

http://www.ncbi.nlm.nih.gov/pubmed/27506815

Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting.

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“Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic.

If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea-a conditioned response to the contextual cues associated with illness-inducing chemotherapy-can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options.

One of the first documented medicinal uses of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV.

Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.”

http://www.ncbi.nlm.nih.gov/pubmed/27507945