“The isolation from Cannabis sativa L. of an inhibitor of prostaglandin (PG) E2 production by cultured rheumatoid synovial cells is described. This agent, for which the name Cannflavin has been coined, is distinct from cannabinoids on the basis of isolation procedure, preliminary structural analysis and biological properties. The activity of Cannflavin has been compared with several established anti-inflammatory drugs and the major cannabinoids.”
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Cannflavins from hemp sprouts, a novel cannabinoid-free hemp food product, target microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase
“Hemp seeds are of great nutritional value, containing all essential amino acids and fatty acids in sufficient amount and ratio to meet the dietary human demand.
Hemp seeds do not contain cannabinoids, and because of their high contents of ω-3 fatty acids, are enjoying a growing popularity as a super-food to beneficially affect chronic inflammation.
Seeds also lack the typical phenolics of hemp leaves and inflorescences, but we found that sprouting, while not triggering the production of cannabinoids, could nevertheless induce the production of the anti-inflammatory prenylflavonoids cannflavins A and B.
This effect was especially marked in Ermo, a cannabinoid-free variety of Cannabis sativa L. Microsomal prostaglandin E2 synthase (mPGES-1) and 5-lipoxygenase (5-LO) were identified as the molecular targets of cannflavins A and B, solving an almost three-decade old uncertainty on the mechanism of their the anti-inflammatory activity.
No change on the fatty acid profile was observed during sprouting, and the presence of lipophilic flavonoids combines with the high concentration of ω-3 essential acids to qualify sprouts from Ermo as a novel anti-inflammatory hemp food product worth considering for mass production and commercial development.”
http://www.sciencedirect.com/science/article/pii/S2213434414000176
Medical Marijuana Laws Reduce Prescription Medication Use In Medicare Part D.
“Legalization of medical marijuana has been one of the most controversial areas of state policy change over the past twenty years. However, little is known about whether medical marijuana is being used clinically to any significant degree. Using data on all prescriptions filled by Medicare Part D enrollees from 2010 to 2013, we found that the use of prescription drugs for which marijuana could serve as a clinical alternative fell significantly, once a medical marijuana law was implemented. National overall reductions in Medicare program and enrollee spending when states implemented medical marijuana laws were estimated to be $165.2 million per year in 2013. The availability of medical marijuana has a significant effect on prescribing patterns and spending in Medicare Part D.” http://www.ncbi.nlm.nih.gov/pubmed/27385238
“Medical Marijuana Laws Reduce Prescription Medication Use In Medicare Part D” https://www.healthaffairs.org/doi/abs/10.1377/hlthaff.2015.1661
The endocannabinoid system – a target for the treatment of LUTS?
“Lower urinary tract symptoms (LUTS) are common in all age groups and both sexes, resulting in tremendous personal suffering and a substantial burden to society.
Antimuscarinic drugs are the mainstay of symptom management in patients with LUTS, although their clinical utility is limited by the high prevalence of adverse effects, which often limit patients’ long-term adherence to these agents.
Data from controversial studies in the 1990s revealed the positive effects of marijuana-based compounds on LUTS, and sparked an interest in the possibility of treating bladder disorders with cannabis.
Increased understanding of cannabinoid receptor pharmacology and the discovery of endogenous ligands of these receptors has prompted debate and further research into the clinical utility of exogenous cannabinoid receptor agonists relative to the unwanted psychotropic effects of these agents.
Currently, the endocannabinoid system is considered as a potential drug target for pharmacological management of LUTS, with a more favourable adverse event profile than antimuscarinic agents.”
The cannabinoid 2 receptor agonist β-caryophyllene modulates the inflammatory reaction induced by Mycobacterium bovis BCG by inhibiting neutrophil migration.
“β-Caryophyllene (BCP) is a sesquiterpene that binds to the cannabinoid 2 (CB2) receptor and exerts anti-inflammatory effects. In this study, we investigated the anti-inflammatory effect of BCP and another CB2 agonist, GP1a in inflammatory experimental model induced by Mycobacterium bovis (BCG).
These results suggest that the CB2 receptor may represent a new target for modulating the inflammatory reaction induced by mycobacteria.”
http://www.ncbi.nlm.nih.gov/pubmed/27379721
“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
Microglia activation states and cannabinoid system: Therapeutic implications.
“Microglial cells are recognized as the brain’s intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-called phenotypes that depending on the local environment involve them in neuroinflammation, tissue repair and even the resolution of the inflammatory process.
There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity.
Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs.
The expression of cannabinoid receptors – mainly CB2 – and the production of eCBs have been related to the activation profile of these cells and therefore, the microglial phenotype, emerging as one of the mechanisms by which microglia becomes alternatively activated.
Here, we will discuss recent studies that provide new insights into the role of CBs and their endogenous counterparts in defining the profile of microglia activation.
These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.”
Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB.
“One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence.
In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects.
Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids.”
Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.
“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”
Anatomical characterization of the cannabinoid cb1 receptor in cell type-specific mutant mouse rescue models.
“Type-1 cannabinoid (CB1 ) receptors are widely distributed in the brain. Their physiological roles depend on their distribution pattern that differs remarkably among cell types. Hence, subcellular compartments with little but functional relevant CB1 receptors can be overlooked, fostering an incomplete mapping. To overcome this, knock-in mice with cell-type specific rescue of CB1 receptors have emerged as excellent tools to investigate its cell type-specific localization and sufficient functional role with no bias.
However, to know whether these rescue mice maintain endogenous CB1 receptor expression level, detailed anatomical studies are called for. The subcellular distribution of hippocampal CB1 receptors of rescue mice that express the gene exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1 -RS) or GABAergic neurons (GABA-CB1 -RS) was studied by immunoelectron microscopy. Results were compared with conditional CB1 receptor knock-out lines.
As expected, CB1immunoparticles appeared at presynaptic plasmalemma making asymmetric and symmetric synapses. In the hippocampal CA1 stratum radiatum, the values of the CB1 receptor immunopositive excitatory and inhibitory synapses were: Glu-CB1 -RS: 21.89% (glutamatergic terminals); 2.38% (GABAergic terminals); GABA-CB1 -RS: 1.92% (glutamatergic terminals); 77.92% (GABAergic terminals). The proportion of CB1 receptor immunopositive excitatory and inhibitory synapses in the inner third of the dentate molecular layer was: Glu-CB1 -RS: 53.19% (glutamatergic terminals); 2.30% (GABAergic terminals); GABA-CB1 -RS: 3.19% (glutamatergic terminals); 85.07% (GABAergic terminals).
Taken together, Glu-CB1 -RS and GABA-CB1 -RS mice show the usual CB1 receptor distribution and expression in hippocampal cell types with specific rescue of the receptor, being therefore ideal for in-depth anatomical and functional investigations of the endocannabinoid system.”
The multiple waves of cannabinoid 1 receptor signaling.
“The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptor (GPCR) in the CNS with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB1Rs may signal in three different spatiotemporal waves.
The first wave is transient (<10 minutes) and is initiated by heterotrimeric G proteins followed by a second wave (>10 minutes) mediated by beta-arrestins. A final third wave occurs at intracellular compartments and could be elicited by G proteins or beta-arrestins.
This functional complexity presents multiple challenges, from the correct classification of receptor ligands to the identification of the signaling pathways regulated by each wave and their underlying molecular mechanisms and physiological impact.
Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system.
Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from CB1R. The identification of mutations in the receptor that can bias signaling to specific pathways and the use of siRNA technology in combination with toxins have been key tools to identify which signaling cascades are controlled by G proteins or beta-arrestins.
Here, we review our current knowledge of the multiple waves of CB1R signaling with particular emphasis on the mechanisms and cascades mediated by beta-arrestins downstream from the CB1R.”