“The orphan G protein-coupled receptor 6 (GPR6) displays unique promise as a therapeutic target for the treatment of neuropsychiatric disorders due to its high expression in the striatopallidal neurons of the basal ganglia. GPR6, along with closely related orphan receptors GPR3 and GPR12, are phylogenetically related to CB1 and CB2 cannabinoid receptors. In the current study, we performed concentration-response studies on the effects of three different classes of cannabinoids: endogenous, phyto-, and synthetic, on both GPR6-mediated cAMP accumulation and β-arrestin2 recruitment. In addition, structure-activity relationship studies were conducted on cannabidiol (CBD), a recently discovered inverse agonist for GPR6. We have identified four additional cannabinoids, cannabidavarin (CBDV), WIN55212-2, SR141716A and SR144528, that exert inverse agonism on GPR6. Furthermore, we have discovered that these cannabinoids exhibit functional selectivity toward the β-arrestin2 recruitment pathway. These novel, functionally selective inverse agonists for GPR6 can be used as research tools and potentially developed into therapeutic agents.” https://www.ncbi.nlm.nih.gov/pubmed/30480157]]>
Category Archives: Endocannabinoid System
Aerobic Fitness Level Moderates the Association Between Cannabis Use and Executive Functioning and Psychomotor Speed Following Abstinence in Adolescents and Young Adults.
“The high rate of cannabis (CAN) use in emerging adults is concerning given prior research suggesting neurocognitive deficits associated with CAN use in youth. Regular CAN use downregulates endocannabinoid activity, while aerobic exercise upregulates cannabinoid receptor 1 activity and releases endocannabinoids. Here we investigate the influence of regular CAN use on neuropsychological performance, and whether aerobic fitness moderates these effects.
RESULTS:
Increased CAN use was associated with decreased performance on working memory and psychomotor tasks. High aerobic fitness level was related to better performance on visual memory, verbal fluency, and sequencing ability. CAN*VO2 max predicted performance of psychomotor speed, visual memory, and sequencing ability.CONCLUSIONS:
Following monitored abstinence, increased CAN use was associated with poorer performance in working memory and psychomotor speed. Higher aerobic fitness level moderated the impact of CAN on visual memory, executive function and psychomotor speed, as more aerobically fit CAN users demonstrated better performance relative to low-fit users. Therefore, aerobic fitness may present an affordable and efficacious method to improve cognitive functioning in CAN users.” https://www.ncbi.nlm.nih.gov/pubmed/30474579 https://www.cambridge.org/core/journals/journal-of-the-international-neuropsychological-society/article/aerobic-fitness-level-moderates-the-association-between-cannabis-use-and-executive-functioning-and-psychomotor-speed-following-abstinence-in-adolescents-and-young-adults/B033EA73E6C1FBFFBC75F45CC426C1CC“Exercise activates the endocannabinoid system.” https://www.ncbi.nlm.nih.gov/pubmed/14625449
]]>Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity.
“A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart.
Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1.
Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.”
https://www.ncbi.nlm.nih.gov/pubmed/30472964
https://link.springer.com/article/10.1134%2FS0006297918100127
Cannabinoids as Regulators of Neural Development and Adult Neurogenesis
“Neurogenesis plays an indispensable role in the formation of the nervous system during development. The discovery that the adult brain still maintains neurogenic niches that allow the continued production of new cells after birth has changed the field of neuroscience. It has also opened a new venue of opportunities for the treatment of central nervous system disorders related to neuronal loss. This chapter has reviewed the studies showing that genetic or pharmacological manipulation of cannabinoid receptors (CB1 and CB2) or the enzymes responsible for endocannabinoid metabolism modify/regulate cell proliferation and neurogenesis during development and in the adult brain. A better characterization of the mechanisms involved in these effects could contribute to the development of new therapeutic alternatives to neurodegenerative and psychiatric disorders.” https://link.springer.com/chapter/10.1007/978-3-319-49343-5_6?fbclid=IwAR1yxGqvrq_9Zva3HLEqjh2WrNRTxPN6Hy_IO8l2IN8v9BCNBG2jDks9N1w]]>
Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.
“Neuroinflammation plays a vital role in Alzheimer’s disease and other neurodegenerative conditions. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia.
Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer’s disease, Parkinson, and multiple sclerosis (MS).”
https://www.ncbi.nlm.nih.gov/pubmed/30453998 https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1362-7 “Pharmacological characterization of GPR55, a putative cannabinoid receptor.” https://www.ncbi.nlm.nih.gov/pubmed/20298715 “Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/]]>The Highs and Lows of the Endocannabinoid System—Another Piece to the Epilepsy Puzzle?
“Cannabis extracts have been used for the treatment of epilepsy for centuries. Yet, until recently, this empirical use was not linked to a known mechanism of action. Of the two main and most frequently investigated compounds derived from the cannabis plant, the mechanism of action of tetrahydrocannabinol (THC) is relatively clear and well documented (via CB1R distributed mainly centrally and CB2R distributed mainly peripherally). The components of endocannabinoid system (ECS) are omnipresent in our bodies and have very divergent roles. Modulating ECS may have therapeutic potential in many human maladies, including psychiatric disorders (e.g., depression, posttraumatic stress disorder, anxiety, or schizophrenia), neurologic conditions, including epilepsy and neurodegenerative processes, diabetes and its complications, obesity, pain management, cancer treatment, graft versus host disease, treatment of chemotherapy side effects, and so on. The list is long, and it is constantly growing. We investigated changes in the endocannabinoid system and glucose metabolism during temporal lobe epileptogenesis.
This study provides unique evidence that the CB1R is dynamically and progressively involved from the start of mesial temporal lobe epileptogenesis.”
http://epilepsycurrents.org/doi/10.5698/1535-7597.18.5.315Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle.
“Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders.
The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews.
It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response.
Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia.
Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.”
https://www.ncbi.nlm.nih.gov/pubmed/30464888
“Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms.
In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.”
“New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia.
Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult.
In the present study, we examined NSCs exposed to IL-1β in vitro to assess inflammation-caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury.
Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and that GPR55 provides a novel therapeutic target against negative regulation of hippocampal neurogenesis by inflammatory insult.”