Age-related changes in the endocannabinoid system in the mouse hippocampus.

Posted on August 29, 2015 by David

“Previous studies have demonstrated that the endocannabinoid system significantly influences the progression of brain ageing, and the hippocampus is one of the brain regions most vulnerable to ageing and neurodegeneration.

We have further examined age-related changes in the hippocampalendocannabinoid system by measuring the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in young and old mice from two different mouse strains.

We found a decrease in 2-AG but not AEA levels in aged mice.

In order to identify the cause for 2-AG level changes, we investigated the levels of several enzymes that contribute to synthesis and degradation of 2-AG in the hippocampus.

We found a selective decrease in DAGLα mRNA and protein levels as well as an elevated MAGL activity during ageing.

We hypothesize that the observed decrease of 2-AG levels is probably caused by changes in DAGLα expression and MAGL activity.

This finding can contribute to the existing knowledge about the processes underlying selective vulnerability of the hippocampus to ageing and age-related neurodegeneration.”

http://www.ncbi.nlm.nih.gov/pubmed/26278494

Effect of anandamide on endometrial adenocarcinoma (Ishikawa) cell numbers: implications for endometrial cancer therapy.

Posted on August 29, 2015 by David

The Lancet logo

“We have previously shown that patients with endometrial carcinoma express elevated concentrations of the endocannabinoid, anandamide (AEA), in both their plasma and their endometrial tissue and that the endometrial carcinoma cell line, Ishikawa, contains the receptors to which AEA binds.

Several studies have reported that human and rodent cancer cell lines die in response to high AEA concentrations.

The incidence of endometrial carcinoma continues to escalate and, although surgical treatment has improved, morbidity and mortality rates have not. A move towards a novel non-surgical therapeutic option is thus required, and the endocannabinoid system provides a good candidate target.

We aimed to investigate the effects of AEA on the survival and proliferation of an endometrial carcinoma cell model.

Our results show that AEA induces a decrease in Ishikawa cell number probably through inhibition of cell proliferation rather than cell death.

These data suggest that the increased plasma and tissue AEA concentrations observed in patients with endometrial cancer is a counter mechanism against further cancer growth and points to the endocannabinoid system as a potentially new therapeutic target.”

http://www.ncbi.nlm.nih.gov/pubmed/26312842

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60335-X/fulltext

Cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic stroke in mice.

Posted on August 25, 2015 by David

“Brain ischemia produces neuronal cell death and the recruitment of pro-inflammatory cells.

In turn, the search for neuroprotection against this type of insult has rendered results involving a beneficial role of endocannabinoid receptor agonists in the Central Nervous System.

In this work, to further elucidate the mechanisms associated to this neuroprotective effect…

Motor tests showed a progressive deterioration in motor activity in ischemic animals, which only ACEA treatment was able to counteract.

Our results suggest that CB1R may be involved in neuronal survival and in the regulation of neuroprotection during focal cerebral ischemia in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/26296704

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

Monoacylglycerol Lipase Regulates Fever Response.

Posted on August 21, 2015 by David

“Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.”

http://www.ncbi.nlm.nih.gov/pubmed/26287872

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

Posted on August 19, 2015 by David

“Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana.

The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation.

It is present in both the central nervous system and peripheral organs including the kidney.

The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies.

Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis.

These effects can be chronically ameliorated by CB1 receptor blockers.

In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases.

Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26280171

The Endocannabinoid System and its Modulation by Phytocannabinoids

Posted on August 15, 2015 by David

“The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ9-tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)—cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); their two most studied endogenous ligands, the “endocannabinoids” N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism.

However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB1R and CB2R.

Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with “endocannabinoid-like” mediators that may or may not interact with the same proteins as Δ9-tetrahydrocannabinol and other phytocannabinoids.

In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors.

Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets.

Here, we review the whole world of ligands, receptors, and enzymes, a true “endocannabinoidome”, discovered after the cloning of CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26271952

http://link.springer.com/article/10.1007%2Fs13311-015-0374-6

Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors.

Posted on August 10, 2015 by David

“Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation.

LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors.

Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors.

In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain…

This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test.

Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A.

These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.”

http://www.ncbi.nlm.nih.gov/pubmed/26254729

Endocannabinoid Signaling in Autism.

Posted on July 29, 2015 by David

“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.

Posted on July 29, 2015 by David

“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

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

Posted on July 24, 2015 by David

“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