Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists As Potential Treatment for Inflammatory Kidney Diseases.

“The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis.

A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen…

A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis.

Oral treatment with 39 at 3 mg kg-1 per day significantly decreased the amount of fibrosis by ∼40 % which was induced by unilateral ureter obstruction.”

http://www.ncbi.nlm.nih.gov/pubmed/26228928

ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs.

“Hippocampal neurogenesis plays a very important role in learning and memory functions.

In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties.

The aim of this study was to evaluate the impact of ACEA (arachidonyl-2′-chloroethylamide – a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells’ proliferation and differentiation in the mouse brain.

VPA administered alone decreased the number of newly born neurons with no significant impact on neurogenesis.

These data provide substantial evidence that VPA administered chronically slightly decreases the proliferation and differentiation of newly born cells while combination of VPA+ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.”

http://www.ncbi.nlm.nih.gov/pubmed/26225920

The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma.

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“The endocannabinoid system plays protective roles against the growth and the spreading of several types of carcinomas.

Because estrogens regulate this system both in physiological states and cancer, in this paper we evaluated its involvement in endometrial carcinoma, a well-known estrogen-dependent tumor.

In conclusion, the endocannabinoid system seems to play an important role in human endometrial carcinoma, and modulation of CB(2) activity/expression may account for a tumor-suppressive effect.”

http://www.ncbi.nlm.nih.gov/pubmed/20133454

https://academic.oup.com/endo/article/151/3/921/2456492

Endocannabinoid Signaling in Autism.

“Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions).

In the last 25 years a good deal of information has been accumulated on the main components of the “endocannabinoid (eCB) system”, a rather complex ensemble of lipid signals (“endocannabinoids”), their target receptors, purported transporters, and metabolic enzymes.

It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders.

Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.”

http://www.ncbi.nlm.nih.gov/pubmed/26216231#

http://www.thctotalhealthcare.com/category/autism/

COMPARATIVE EFFECTS OF PARATHION AND CHLORPYRIFOS ON ENDOCANNABINOID AND ENDOCANNABINOID-LIKE LIPID METABOLITES IN RAT STRIATUM.

“Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE).

The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems.

Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications.”

http://www.ncbi.nlm.nih.gov/pubmed/26215119

Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor.

“Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1 ).

We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1…

Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 .

Allosteric modulation, in conjunction with non-CB1 effects, may explain the in vivo effects of cannabidiol.

Allosteric modulators of CB1 have the potential to treat central nervous system and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of CB1.”

http://www.ncbi.nlm.nih.gov/pubmed/26218440

Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model.

“Cannabinoid pharmacology has proven nettlesome with issues of promiscuity a common theme among both agonists and antagonists.

One recourse is to develop allosteric ligands to modulate cannabinoid receptor signaling.

Cannabinoids have come late to the allosteric table…

In summary, three of the allosteric modulators evaluated function in a manner consistent with allosterism in a neuronal 2-AG-based model of endogenous cannabinoid signaling.”

http://www.ncbi.nlm.nih.gov/pubmed/26211948

Synergistic anti-allodynic effects of nociceptin/orphanin FQ and cannabinoid systems in neuropathic mice.

“Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects.

The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain…

In conclusion, co-administration of acannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/21664922

Cannabinoids for the Treatment of Movement Disorders.

“Use of cannabinoids as medications has a long history.

Unfortunately, the prohibition of cannabis and its classification in 1970 as a schedule 1 drug has been a major obstacle in studying these agents in a systematic, controlled manner.

The number of class 1 studies (randomized, double-blind, placebo-controlled) in patients with movement disorders is limited. Hence, it is not possible to make recommendations on the use of these cannabinoids as primary treatments for any of the movement disorders at this time.

Fortunately, there is an expanding body of research in animal models of age-dependent and disease-related changes in the endocannabinoid system that is providing new targets for drug development.

Moreover, there is growing evidence of a “cannabinoid entourage effect” in which a combination of cannabinoids derived from the plant are more effective than any single cannabinoid for a number of conditions.

Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective.

As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will expand.”

http://www.ncbi.nlm.nih.gov/pubmed/26206230

The endocannabinoid anandamide affects the synthesis of human syncytiotrophoblast-related proteins.

“The human syncytiotrophoblast (hST) has a major role in the production of important placental hormones.

Several molecules regulate hST endocrine function but the role of endocannabinoids in this process is still unknown.

Here, we report that the endocannabinoid anandamide (AEA) decreased cAMP levels, impaired human chorionic gonadotropin secretion, placental alkaline phosphatase activity and decreased aromatase mRNA levels and protein expression, through cannabinoid (CB) receptor activation.

AEA also downregulated leptin and placental protein 13 transcription, though via a CB receptor-independent mechanism.

All this evidence suggests AEA is a novel modulator of hormone synthesis by the syncytiotrophoblast, supporting the importance of the endocannabinoid signalling in placental function.”

http://www.ncbi.nlm.nih.gov/pubmed/26202891