Tag Archives: 2-AG

Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

Posted on by
Reply

“Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level…

The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing.

SIGNIFICANCE STATEMENT:

Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval.

These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.”

http://www.ncbi.nlm.nih.gov/pubmed/26468197

Endocannabinoids and the Immune System in Health and Disease.

Posted on by
Reply

“Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of immune cells.

Their activation of these seven-transmembranal, G protein-coupled receptors sets in motion a series of signal transductional events that converge at the transcriptional level to regulate cell migration and the production of cytokines and chemokines.

There is a large body of data that supports a functional relevance for 2-arachidonoylglycerol (2-AG) as acting through the cannabinoid receptor type 2 (CB2R) to inhibit migratory activities for a diverse array of immune cell types.

However, unequivocal data that supports a functional linkage of anandamide (AEA) to a cannabinoid receptor in immune modulation remains to be obtained.

Endocannabinoids, as typical bioactive lipids, have a short half-life and appear to act in an autocrine and paracrine fashion.

Their immediate effective action on immune function may be at localized sites in the periphery and within the central nervous system.

It is speculated that endocannabinoids play an important role in maintaining the overall “fine-tuning” of the immune homeostatic balance within the host.”

http://www.ncbi.nlm.nih.gov/pubmed/26408161

Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

Posted on by
Reply

“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.

Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.

These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.

In addition, many cell types in synovial tissue express CB1 and TRPs.

In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.

We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.

The concept of functional antagonism with continuous CB1 activation is discussed.

Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.

Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26343051

Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease.

Posted on by
Reply

“Parkinson’s disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain.

Symptomatic therapies are available but no treatment slows or prevents the loss of neurons.

Neuroinflammation has been implicated in its pathogenesis.

To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients.

Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated.

The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death.

Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects.

Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits.

The results expand the current understanding of the role that this signalling system has and its potential influence in PD.”

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

Posted on by
Reply

“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

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

Posted on by
Reply

“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 by
Reply

“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

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

Posted on by
Reply

“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

Elucidating Cannabinoid Biology in Zebrafish (Danio rerio).

Posted on by
Reply

“Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health.

Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions.

Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling.

The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model-focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol.

Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors.

These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies.

This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation.”

http://www.ncbi.nlm.nih.gov/pubmed/26192460

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis.

Posted on by
Reply

“Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system.

Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)…

These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26189763