2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons.

Posted on March 31, 2015 by David

“The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means…

Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons.”

http://www.ncbi.nlm.nih.gov/pubmed/25814137

http://www.thctotalhealthcare.com/category/post-traumatic-stress-disorder-ptsd/

Endocannabinoid signaling at the periphery: 50 years after THC.

Posted on March 23, 2015 by David

“In 1964, the psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995.

Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation.

Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered.

Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.”

http://www.ncbi.nlm.nih.gov/pubmed/25796370

The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view.

Posted on March 21, 2015 by David

“The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover.

Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling.

In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view.

It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone.

Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of “cannabis-like” behaviours.”

http://www.ncbi.nlm.nih.gov/pubmed/25791296

Differential expression of endocannabinoid system in normal and preeclamptic placentas: effects on nitric oxide synthesis.

Posted on March 4, 2015 by David

“Anandamide (AEA) is a lipid mediator that participates in the regulation of several reproductive functions.

This study investigated the endocannabinoid system in normal (NP) and preeclamptic (PE) placentas, and analyzed the potential functional role of AEA in the regulation of nitric oxide synthesis…

These data suggest that AEA may be one of the factors involved in the regulation of NOS activity in normal and preeclamptic placental villous.

Interestingly, the differential expression of NAPE-PLD and FAAH suggests that AEA could play an important role in the pathophysiology of PE.”

http://www.ncbi.nlm.nih.gov/pubmed/23122699

Simultaneous inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) shares discriminative stimulus effects with ∆9-THC in mice.

Posted on February 27, 2015 by David

“Δ9 -tetrahydrocannabinol (∆9 -THC) is a cannabinoid CB1 /CB2 receptor agonist that produces therapeutic effects such as analgesia and anti-emetic effects…

Collectively, the current results show that pharmacological increases in endogenous AEA and 2-AG simultaneously through inhibition of FAAH and MAGL, respectively, mimics the discriminative stimulus effects of Δ9 -THC.”

http://jpet.aspetjournals.org/content/early/2015/02/24/jpet.115.222836.long

Fatty Acid Binding Proteins (FABPs) are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

Posted on February 11, 2015 by David

Image result for fatty acid binding proteins

“Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex.

Recent reports suggest that CBD and THC elevates the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance.

Fatty acid binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH).

By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and we demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs.

Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption.

Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD.

Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.

These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy towards epilepsy and other neurological disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25666611

Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase-2 and novel J-series prostamides.

Posted on January 22, 2015 by David

“Non-melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase-2 (COX-2), differentiating them from normal cells…

Arachidonoyl-ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types…

These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX-2 due to the metabolism of AEA by COX-2 to J-series prostaglandin-ethanolamides (prostamides).

Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2.”

http://www.ncbi.nlm.nih.gov/pubmed/25557612

http://www.thctotalhealthcare.com/category/skin-cancer/

Cannabinoid CB1 receptors in the dorsal hippocampus and prelimbic medial prefrontal cortex modulate anxiety-like behavior in rats: additional evidence.

Posted on January 18, 2015 by David

“Endocannabinoids (ECBs) such as anandamide (AEA) act by activating cannabinoid type 1 (CB1) or 2 (CB2) receptors. The anxiolytic effect of drugs that facilitate ECB effects is associated with increase in AEA levels in several encephalic areas, including the prefrontal cortex (PFC).

Activation of CB1 receptors by CB1 agonists injected directly into these areas is usually anxiolytic.

However, depending on the encephalic region being investigated and on the stressful experiences, opposite effects were observed, as reported in the ventral HIP. In addition, contradictory results have been reported after CB1 activation in the dorsal HIP (dHIP).

Therefore, in the present paper we have attempted to verify if directly interfering with ECB metabolism/reuptake in the prelimbic (PL) portion of the medial PFC (MPFC) and dHIP would produce different effects in two conceptually distinct animal models: the elevated plus maze (EPM) and the Vogel conflict test (VCT).

We observed drugs which interfere with ECB reuptake/metabolism in both the PL and in the dentate gyrus of the dHIP induced anxiolytic-like effect, in both the EPM and in the VCT via CB1 receptors, suggesting CB1 signaling in these brain regions modulate defensive responses to both innate and learned threatening stimuli.

This data further strengthens previous results indicating modulation of hippocampal and MPFC activity via CB1 by ECBs, which could be therapeutically targeted to treat anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25595265

http://www.thctotalhealthcare.com/category/anxiety-2/

Endocannabinoids, Related Compounds and Their Metabolic Routes.

Posted on October 28, 2014 by David

“Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol.

These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, their main representatives.

During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds) have been discovered and their activities biological is the subject of intense investigations.

Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/25347455

Endocannabinoid signaling and epidermal differentiation.

Posted on July 27, 2014 by David

“Endocannabinoids represent a class of endogenous lipid mediators, that are involved in various biological processes, both centrally and peripherally. The prototype member of this group of compounds, anandamide, regulates cell growth, differentiation and death; this holds true also in the skin, that is the largest organ of the body constantly exposed to physical, chemical, bacterial and fungal challenges.

The epidermis is a keratinized multistratified epithelium that functions as a barrier to protect the organism from dehydration, mechanical trauma, and microbial insults, and epidermal differentiation represents one of the best characterized mechanisms of cell specialization.

In this review, we shall summarize current knowledge about the main members of the so-called “endocannabinoid system (ECS)”, in order to put in a better perspective the manifold roles that they play in skin pathophysiology.

In particular, we shall discuss some aspects of the molecular regulation by endocannabinoids of proliferation and terminal differentiation (“cornification”) of mammalian epidermis, showing that ECS is finely regulated by, and can interfere with, the differentiation program.

In addition, we shall review evidence demonstrating that disruption of this fine regulation might cause different skin diseases, such as acne, seborrhoea, allergic dermatitis, itch, psoriasis and hair follicle regression (catagen), making of ECS an attractive target for therapeutic intervention.”

http://www.ncbi.nlm.nih.gov/pubmed/21628127