Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome.

toxins-logo “In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.”

https://www.ncbi.nlm.nih.gov/pubmed/31096702

https://www.mdpi.com/2072-6651/11/5/275

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The effects of delta-9-tetrahydrocannabinol on Krüppel-like factor-4 expression, redox homeostasis, and inflammation in the kidney of diabetic rat.

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“Diabetes mellitus is a complex, multifactorial disorder that is attributed to pancreatic β cell dysfunction. Pancreatic β cell dysfunction results in declining utilization of glucose by peripheral tissues as kidney and it leads to nephropathy. Excessive production and accumulation of free radicals and incapable antioxidant defense system lead to impaired redox status. Macromolecular damage may occur due to impaired redox status and also immune imbalance.

Δ9-Tetrahydrocannabinol (THC) is the main active ingredient in cannabis. THC acts as an immunomodulator and an antioxidant agent.

Our aim was to evaluate the effects of THC in the diabetic kidney.

According to our data, THC has ameliorative effects on the impaired redox status of diabetic kidney and also it acts as an immunomodulator. Therefore, THC might be used as a therapeutic agent for diabetic kidneys but its usage in the healthy kidney may show adverse effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31081965

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcb.28903

“Marijuana Doesn’t Seem to Harm the Kidneys” https://www.webmd.com/mental-health/addiction/news/20180306/marijuana-doesnt-seem-to-harm-the-kidneys

“Pot Won’t Harm Healthy Young People’s Kidneys, Study Suggests”   https://www.medicinenet.com/script/main/art.asp?articlekey=206375

“Marijuana doesn’t appear to harm kidneys”   https://www.hsph.harvard.edu/news/hsph-in-the-news/marijuana-kidneys/

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Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications.

ijms-logo “Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/31035653

https://www.mdpi.com/1422-0067/20/9/2109

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A patent update on cannabinoid receptor 1 antagonists (2015-2018).

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“The endocannabinoid system is an important regulator of various physiological processes. Preclinical and clinical studies indicate that attenuation of the endocannabinoid system via antagonism of the type 1 cannabinoid receptor (CB1) is an excellent strategy to treat obesity, metabolic syndrome and associated disorders. However, centrally acting antagonists of CB1 also produce adverse effects like depression and anxiety. Current efforts are geared towards discovery and optimization of antagonists and modulators of CB1 that have limited brain penetration. Areas Covered: Several recent publications and patent applications support the development of peripherally acting CB1 receptor antagonists and modulators. In this review, recent patents and applications (2015 – 2018) are summarized and discussed. Expert Opinion: Approximately 30 new inventions have been reported since 2015, along with 3 recent commercial deals, highlighting the importance of this class of therapeutics. Taken together, peripherally acting CB1 receptor antagonists and modulators are an emerging class of drugs for metabolic syndrome, non-alcoholic steatohepatitis (NASH) and other important disorders where this receptor has been implicated.”

https://www.ncbi.nlm.nih.gov/pubmed/30889997

https://www.tandfonline.com/doi/abs/10.1080/13543776.2019.1597851?journalCode=ietp20

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Cannabidiol attenuates mechanical allodynia in streptozotocin-induced diabetic rats via serotonergic system activation through 5-HT1A receptors.

Brain Research

“Most diabetic patients describe moderate to severe pain symptoms whose pharmacological treatment is palliative and poorly effective. Cannabidiol (CBD) has shown promising results in painful conditions. Then, we aimed to investigate the potential antinociceptive effect of CBD over the mechanical allodynia in streptozotocin-induced diabetic (DBT) rats, as well as its involved mechanisms. Wistar adult male diabetic rats were treated acutely or sub-chronically (for 14 days) with CBD (0.1, 0.3 or 3 mg/Kg, intraperitoneal; i.p.) and had their mechanical threshold assessed using the electronic Von Frey. Acute treatment with CBD (at doses of 0.3 and 3 mg/Kg) exerted a significant anti-allodynic effect, which is not associated with locomotor impairment. The antinociceptive effect of CBD (3 mg/Kg) was not altered by the pre-treatment with CB1 or CB2 receptor antagonists (AM251 and AM630; respectively; both at a dose of 1 mg/kg, i.p.) nor by glycine receptor antagonist (strychnine hydrochloride, 10 μg/rat, intrathecal, i.t.). However, this effect was completely prevented by the pre-treatment with the selective 5-HT1A receptor antagonist WAY 100135 (3 μg/rat, i.t.). Sub-chronic treatment with CBD (0.3 or 3 mg/Kg) induced a sustained attenuation of the mechanical allodynia in DBT rats. DBT rats presented significantly lower spinal cord levels of serotonin, which was prevented by the daily treatment with CBD (0.3 mg/Kg). Taken together, our data suggest that CBD may be effective in the treatment of painful diabetic neuropathy and this effect seems to be potentially mediated by the serotonergic system activation through 5-HT1A receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30898678

https://www.sciencedirect.com/science/article/pii/S0006899319301532?via%3Dihub

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β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice.

 View details for Journal of Medicinal Food cover image“Neuropathic pain (NP) is associated with chronic hyperglycemia and emotional disorders such as depression in diabetic patients, complicating the course of treatment. Drugs currently used to treat NP have undesirable side effects, so research on other natural sources has been required.

β-caryophyllene (BCP), a natural sesquiterpene found in some food condiments and considered an agonist to cannabinoid receptor type 2, could have potential therapeutic effects to treat conditions such as NP and emotional disorders. For this reason, we assessed whether BCP modulates nociception, anxiety, and depressive-like behavior in streptozotocin (STZ)-induced experimental diabetic BALB/c female mice.

BCP was orally chronic administrated (10 mg/kg/60 μL). Pain developed with STZ was evaluated with von Frey filament test, SMALGO®, and hot plate test. Anxiety and depression-like behavior were assessed by marbles test, forced swim test, and tail suspension test. BCP significantly reduced glycemia in experimental diabetic mice. The pain was also mitigated by BCP administration. Depression-like behavior assessed with tail suspension test was attenuated with orally chronic BCP administration. Substance P and cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were also attenuated with BCP administration. NP was positively correlated with substance P and IL-6 and IL-1β release.

Our data using an orally chronic BCP administration in the STZ challenged mice to suggest that glycemia, diabetes-related NP, and depressive-like behavior could be prevented/reduced by dietary BCP.”

https://www.ncbi.nlm.nih.gov/pubmed/30864870

https://www.liebertpub.com/doi/10.1089/jmf.2018.0157

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Novel protective effect of O-1602 and abnormal cannabidiol, GPR55 agonists, on ER stress-induced apoptosis in pancreatic β-cells.

Biomedicine & Pharmacotherapy

“Insulin resistance and β-cell dysfunction are the main defects in Type 2 Diabetes Mellitus (T2DM), and β-cell dysfunction and apoptosis is the critical determinant in the progression of T2DM. G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by endocannabinoids and lipid transmitters. Recently, GPR55 was shown to regulate glucose and energy homeostasis, however its role in β-cell apoptosis was not studied. Therefore, in this study, we investigated the novel effect of GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on endoplasmic reticulum (ER) stress-induced apoptosis in mouse pancreatic β-cell lines, MIN6 and Beta-TC-6, and its underlying mechanisms. Our results showed that O-1602 and Abn-CBD reduced ER stress-induced apoptosis in MIN6 and Beta-TC-6 cells. This was through the phosphorylation of 3′-5′-cyclic adenosine monophosphate response element-binding protein (CREB) in β-cells, hence activating CREB downstream anti-apoptotic genes, Bcl-2 and Bcl-xL. Moreover, O-1602 and Abn-CBD directly activated kinases, CaMKIV, Erk1/2 and PKA, to induce CREB phosphorylation. Therefore, our results indicated that GPR55 agonists protected from β-cell apoptosis through CREB activation, thus up-regulating anti-apoptotic genes. In conclusion, our study provided a novel protective effect of GPR55 agonists on ER stress-induced apoptosis in β-cells and its underlying mechanisms mediating this protection, therefore we suggested that GPR55 might be a therapeutic target for T2DM.”

https://www.ncbi.nlm.nih.gov/pubmed/30841431

https://www.sciencedirect.com/science/article/pii/S0753332218375668?via%3Dihub

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[MEDICAL CANNABIS – A SOURCE FOR A NEW TREATMENT FOR AUTOIMMUNE DISEASE?].

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“Medical uses of Cannabis sativa have been known for over 6,000 years. Nowadays, cannabis is mostly known for its psychotropic effects and its ability to relieve pain, even though there is evidence of cannabis use for autoimmune diseases like rheumatoid arthritis centuries ago. The pharmacological therapy in autoimmune diseases is mainly based on immunosuppression of diffefent axes of the immune system while many of the drugs have major side effects. In this review we set out to examine the rule of Cannabis sativa as an immunomodulator and its potential as a new treatment option. In order to examine this subject we will focus on some major autoimmune diseases such as diabetes type I and rheumatoid arthritis.”

https://www.ncbi.nlm.nih.gov/pubmed/27215114

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Do Endocannabinoids Regulate Glucose Reabsorption in the Kidney?

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“Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood.

Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN.

Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs.

These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN.”

https://www.ncbi.nlm.nih.gov/pubmed/30636250

https://www.karger.com/Article/FullText/494512

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The effects of cannabinoids on the endocrine system.

“Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil.

These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells.

Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads.

Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.”

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