“Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associates impaired autophagy, increased activity in the endocannabinoid system and upregulation of suppressor of cytokine signaling (SOCS)-3 protein expression during intestinal inflammatory states. We have investigated whether these three processes are linked. By assessing the impact of phyto-cannabinoid cannabidiol (CBD), synthetic cannabinoid (ACEA) and endocannabinoid (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated CaCo2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid receptor (CB)-1 mediated. In contrast, CBD was able to bypass both the CB1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking both early and late autophagy. In conclusion, the regulatory protein, SOCS3, is itself regulated by autophagy and cannabinoids play a role in this process, which could be important when considering therapeutic applications for the cannabinoids in inflammatory conditions.”
Tag Archives: CB(1) and CB(2) receptors
Getting High on the Endocannabinoid System
“The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health.
Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind.
By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.
…either stimulating or inhibiting the endocannabinoid system could have beneficial effects.
The most direct route of THC administration is by smoking marijuana or other forms of cannabis. Yet purified, FDA-approved medicinal preparations of THC are available in pill form… Why not just take a pill? There are several reasons that some patients prefer puffing over swallowing. One quantitatively minor factor is potential lethality.
It is possible to get a fatal overdose by swallowing too many THC pills at once, whereas documented evidence of death simply from smoking too much cannabis does not seem to exist.”
The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells.
“…there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death. There is emerging evidence that cannabinoids, especially Delta(9)-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival.
Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells…
The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.”
Cannabinoids for pain and nausea
“This is an exciting time for cannabinoid research. The discovery of cannabinoid CB1receptors (expressed by central and peripheral neurones) and CB2 receptors (expressed mainly by immune cells) and endogenous agonists for these receptors has renewed the scientific community’s interest. Independently of these developments society at large has continued an aggressive debate about the therapeutic use of cannabinoids, including demands for their more liberal availability. Cannabinoids have been suggested to have therapeutic value as analgesics and in various conditions, including migraine headaches, nausea and vomiting, wasting syndrome and appetite stimulation in HIV-infected patients, muscle spasticity due to multiple sclerosis or spinal cord injury, movement disorders such as Parkinson’s disease, epilepsy, and glaucoma.”
Targeting the endocannabinoid system in the treatment of fragile X syndrome.
“Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation.
The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice.
We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5.
Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.”
Delta-9-Tetrahydrocannabinol/Cannabidiol (Sativex®): A Review of Its Use in Patients with Moderate to Severe Spasticity Due to Multiple Sclerosis.
“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants.
The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2)…
THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.
In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks’ double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks’ single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale.
A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥30 % reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment.
Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.”
Exercise, Manual Therapy, and the Endocannabinoid System: Why we’re all inherently potheads
“Have you ever heard of the digestive system? The lymphatic system? How about the muscular and nervous systems? Of course you have. Science has been studying them for years, making breakthroughs in our understanding of their inner workings that have lead to advancements benefited humanity in ways we now take for granted.
How about the endocannabinoid system? Have you heard of that? If your profession has nothing to do with the biological sciences, I would expect the answer to be no (save a few individuals). Don’t feel bad however, I have asked this question to many health and medical professionals that I have taught over the years and have received many a blank stare or look of confusion.
What if I were to tell you that this biological system permeates the entire human body with receptors located in skeletal muscle, the digestive tract, adipose (fat) tissue, and throughout the peripheral and central nervous systems (including the brain)? Again, you would question why this system is not studied, discussed, or even mentioned in most in physiology/health classes.
What if I were to tell you that the Endocannabinoid system (or ECS):
– Helps regulate the central control of energy balance
– Helps regulate metabolic processes (including storage)
– Plays a key role in the maintenance of bone mass
– Regulates intestinal motility
– Promotes/regulates sleep
– Is involved in neuromodulation and immunomodulation in the immune system
– Is involved in modulating insulin sensitivity
– Is involved in the regulation of pain signaling
– And much more”
“Exercise activates the endocannabinoid system.” http://www.ncbi.nlm.nih.gov/pubmed/14625449
“Exercise-induced endocannabinoid signaling is modulated by intensity.” http://www.ncbi.nlm.nih.gov/pubmed/22990628
“Effects of exercise stress on the endocannabinoid system in humans under field conditions.” http://www.ncbi.nlm.nih.gov/pubmed/22101870
Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth.
“Because THC-like compounds are used to inhibit nausea and induce appetite in cancer patients, and anandamide appears to be an endogenous orexigenic mediator, the finding of possible antitumor effect for these substances might have a tremendous potential for therapeutic intervention in preventing the progression of cancer and, at the same time, in alleviating its symptoms.
Because multiple pathways are important for the proliferation of tumor cells and because combination therapies are often more effective than single-drug administration, cannabimimetic substances may complement other anticancer agents…”
http://www.fasebj.org/content/early/2001/12/02/fj.01-0320fje.long
“[Targeting the RAS signalling pathway in cancer].” http://www.ncbi.nlm.nih.gov/pubmed/21715253
“Targeting the RAS oncogene.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804031/
Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model.
“Experimental animal models of migraine have suggested the existence of interactions between the endocannabinoid system and pain mediation in migraine.
Extensive evidence has demonstrated a role for the cannabinoid-1 (CB1) receptor in antinociception.
…recent research suggests that also CB2 receptors, especially located outside the central nervous system, play a role in the perception of pain…
In this study we evaluated the role of CB2 receptors in two animal models of pain that may be relevant for migraine…
CONCLUSION:
These findings suggest that the pharmacological manipulation of the CB2 receptor may represent a potential therapeutic tool for the treatment of migraine.”
Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic.
“The limited effectiveness of current therapies against Alzheimer’s disease (AD) highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer.
The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors… Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models…
Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress.
The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of AD, which together encourage progress toward a clinical trial.”
http://www.ncbi.nlm.nih.gov/pubmed/24634659
“Considering the numerous complex pathological mechanisms involved in the progression of AD, treatments targeting a single causal or modifying factor offer limited benefit. Cannabinoids, however, exhibit pleiotropic activity, targeting in parallel several processes that play key roles in AD…”
Full: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942876/