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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Changes in Monoaminergic Neurotransmission in an Animal Model of Osteoarthritis: The Role of Endocannabinoid Signaling.

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“Chronic pain is a main symptom of osteoarthritis (OA). Moreover, a high percentage of OA patients suffer from mental health problems.

The endocannabinoid (EC) system has attracted attention as an emerging drug target for pain treatment together with its activity on the mesolimbic reward system.

Understanding the circuits that govern the reward of pain relief is crucial for the search for effective analgesics. Therefore, we investigated the role of the EC system on dopamine (DA) and noradrenaline (NA) in an animal model of OA-related chronic pain.

Our results demonstrated that chronic pain in OA rats was reflected by the inhibition of mesolimbic and mesocortical dopaminergic transmission, and may indicate the pro-pain role of NA in the FCx.

The data provide understanding about changes in neurotransmission in chronic pain states and may explain the clinical improvement in perceived life quality following cannabinoid treatment.

Additional mechanistic studies in preclinical models examining the intersection between chronic pain and reward circuits may offer new approaches for improving pain therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30618615

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00466/full

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Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies.

“Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory.

OBJECTIVE AND METHODS:

The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated.

RESULTS:

Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen’s d ≥ 1.0). The brain areas responsible for the above mentioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation.

CONCLUSION:

Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.”

https://www.ncbi.nlm.nih.gov/pubmed/30604182

https://link.springer.com/article/10.1007%2Fs00213-018-5127-x

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Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues.

“The endocannabinoid (eCB) system is widely expressed in many central and peripheral tissues, and is involved in a plethora of physiological processes. Among these, activity of the eCB system promotes energy intake and storage, which, however, under pathophysiological conditions, can favour the development of obesity and obesity-related disorders. It is proposed that eCB signalling is evolutionary beneficial for survival under periods of scarce food resources. Remarkably, eCB signalling is increased both in hunger and in overnutrition conditions, such as obesity and type-2 diabetes. This apparent paradox suggests a role of the eCB system both at initiation and at clinical endpoint of obesity. This review will focus on recent findings about the role of the eCB system controlling whole-body metabolism in mice that are genetically modified selectively in different cell types. The current data in fact support the notion that eCB signalling is not only engaged in the development but also in the maintenance of obesity, whereby specific cell types in central and peripheral tissues are key sites in regulating the entire body’s energy homeostasis.”

https://www.ncbi.nlm.nih.gov/pubmed/30599065

https://link.springer.com/article/10.1007%2Fs00018-018-2994-6

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Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users

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“Obesity is treatment-resistant, and is linked with a number of serious, chronic diseases. Adult obesity rates in the United States have tripled since the early 1960s.

Recent reviews show that an increased ratio of omega-6 to omega-3 fatty acids contributes to obesity rates by increasing levels of the endocannabinoid signals AEA and 2-AG, overstimulating CB1R and leading to increased caloric intake, reduced metabolic rates, and weight gain.

Cannabis, or THC, also stimulates CB1R and increases caloric intake during acute exposures.

The present meta-analysis reveals significantly reduced body mass index and rates of obesity in Cannabis users, in conjunction with increased caloric intake.

We provide for the first time a causative explanation for this paradox, in which rapid and long-lasting downregulation of CB1R following acute Cannabis consumption reduces energy storage and increases metabolic rates, thus reversing the impact on body mass index of elevated dietary omega-6/omega-3 ratios.

Evidence suggests that, in the United States, many people may actually achieve net health benefits from moderate Cannabis use, due to reduced risk of obesity and associated diseases.”

https://www.liebertpub.com/doi/10.1089/can.2018.0045?_ga=2.221453528.1791159238.1546024140-1083808004.1546024140

“Reduced Body Mass Index and Obesity Rates in Cannabis Users”  https://www.genengnews.com/insights/reduced-body-mass-index-and-obesity-rates-in-cannabis-users/?fbclid=IwAR3a0wbfGoPwAR-pYQGCeLz-KYUFdiLJoj6Ja7rTTNGBYwkjIGw1fUjf5LI

 

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n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids

 Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids“Anandamide, the first identified endogenous cannabinoid and TRPV1 agonist, is one of a series of endogenous N-acylethanolamines, NAEs. We have generated novel assays to quantify the levels of multiple NAEs in biological tissues and their rates of hydrolysis through fatty acid amide hydrolase. This range of NAEs was also tested in rapid response assays of CB1, CB2 cannabinoid and TRPV1 receptors. The data indicate that PEA, SEA and OEA are not endocannabinoids or endovanilloids, and that the higher endogenous levels of these metabolites compared to polyunsaturated analogues are a correlate of their slow rates of hydrolysis. The n-6 NAEs (AEA, docosatetraenoyl and docosapentaenoyl derivatives) activated both CB1 and CB2 receptors, as well as TRPV1 channels, suggesting them to be ‘genuine’ endocannabinoids and ‘endovanilloids’. The n-3 NAEs (eicosapentaenoyl, docosapentaenoyl and docosahexaenoyl derivatives) activated CB2 receptors and some n-3 NAEs (docosapentaenoyl and docosahexaenoyl derivatives) also activated TRPV1 channels, but failed to activate the CB1 receptor. We hypothesise that the preferential activation of CB2 receptors by n-3 PUFA NAEs contributes, at least in some part, to their broad anti-inflammatory profile.”

https://www.ncbi.nlm.nih.gov/pubmed/30591150

https://www.sciencedirect.com/science/article/pii/S1388198118302026?via%3Dihub

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Bidirectional modulation of food habit expression by the endocannabinoid system.

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“The compulsive, habitual behaviors that have been observed in individuals diagnosed with substance use disorders may be due to disruptions in the neural circuits that mediate goal-directed actions.

The endocannabinoid system has been shown to play a critical role in habit learning, but the role of this neuromodulatory system in habit expression is unclear.

Here, we investigated the role of the endocannabinoid system in established habitual actions using contingency degradation in male C57BL/6 mice.

We found that administration of the endocannabinoid transport inhibitor AM404 reduced habitual responding for food and that antagonism of cannabinoid receptor type 1 (CB1), but not transient receptor potential cation subfamily V (TRPV1), receptors produced a similar reduction in habitual responding.

Moreover, pharmacological stimulation of CB1 receptors increased habitual responding for food. Co-administration of an enzyme inhibitor that selectively increases the endocannabinoid 2-arachidonoyl glycerol (2-AG) with AM404 partially restored habitual responding for food.

Together, these findings demonstrate an important role for the endocannabinoid system in the expression of habits and provide novel insights into potential pharmacological strategies for reducing habitual behaviors in mental disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/30589475

https://onlinelibrary.wiley.com/doi/abs/10.1111/ejn.14330

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Weight loss and improved mood after aerobic exercise training are linked to lower plasma anandamide in healthy people.

Physiology & Behavior

“Anandamide, a major endocannabinoid, participates in energy metabolism homeostasis and neurobehavioral processes. In a secondary analyses of an open-label, randomized controlled trial, we investigated the long-term effect of aerobic exercise on resting plasma anandamide, and explored its relationship with changes in body weight, cardiorespiratory fitness, and mood status in healthy, physically inactive individuals.

Thirty-four participants (age = 38 ± 11.5, BMI = 26.6 ± 3.6) were intention to treat-analysed (Exercise: n = 17; Control: n = 17). After intervention, there were significant decreases in plasma anandamide (p < .01), anger, anxiety, and body weight (all p < .05), whereas cardiorespiratory fitness increased (p < .05) in the exercise group. There were no significant changes in any variable for the control group. In the whole cohort, adjusted R2 of multiple linear regressions showed that 12.2% of change body weight was explained by changes in anandamide (β = 0.391, p = .033), while 27% of change in mood disturbance (β = 0.546, p = .003), and 13.1% of change in anger (β = 0.404, p = .03) was explained by changes in anandamide.

Our data suggest that the weight loss and mood improvement through regular moderate exercise may involve changes in anandamide metabolism/signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/30578894

https://www.sciencedirect.com/science/article/abs/pii/S0031938418308254?via%3Dihub

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Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by drastic alterations in mood, emotions, social abilities and cognition. Notably, one aspect of PTSD, particularly in veterans, is its comorbidity with suicide.

Elevated aggressiveness predicts high-risk to suicide in humans and despite the difficulty in reproducing a complex human suicidal behavior in rodents, aggressive behavior is a well reproducible behavioral trait of suicide. PTSD animal models are based on a peculiar phenotype, including exaggerated fear memory, anxiety- and depressive-like behaviors associated with neurochemical dysregulations in emotional brain circuitry.

The endocannabinoid and the neurosteroid systems regulate emotions and stress responses, and recent evidence shows these two systems are interrelated and critically compromised in neuropsychiatric disorders. For instance, levels of the neurosteroid, allopregnanolone, as well as those of the endocannabinoids, anandamide and its congener, palmitoylethanolamide are decreased in PTSD.

Similarly, the endocannabinoid system and neurosteroid biosynthesis are altered in suicidal individuals.

Selective serotonin reuptake inhibitors (SSRIs), the only FDA-approved treatments for PTSD and depression, fail to help half of the treatment-seeking patients. This highlights the need for developing biomarker-based efficient therapies. One promising hypothesis points to stimulation of allopregnanolone biosynthesis as a valid end-point to predict treatment response in PTSD patients.

This review highlights running findings on the role of the endocannabinoid and neurosteroid systems in PTSD and suicidal behavior both in a preclinical and clinical perspective. A specific focus is given to predictive PTSD/suicide animal models. Ultimately, we discuss the idea that disruption of neurosteroid and endocannabinoid biosynthesis may offer novel promising biomarker candidates to develop new treatments for PTSD and, perhaps, suicidal behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30586627

https://www.sciencedirect.com/science/article/pii/S0278584618305839?via%3Dihub

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