Tag Archives: AEA

The endocannabinoid system: a putative role in neurodegenerative diseases.

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“Scientific evidence shows that an hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s, Parkinson’s and Alzheimer’s diseases.

The aim of this review is to highlight the role of endocannabinoid system in neurodegenerative diseases

Scientific evidence shows that cannabis can provide symptomatic relief in several neurodegenerative diseases such as multiple sclerosis, Huntington’s, Parkinson’s and Alzheimer’s diseases, and amyotrophic lateral sclerosis. These findings imply that a hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of these diseases. Moreover, given the abundance of CB1 receptors in areas associated with movement and executive thought, researchers’ interest has often focused on endocannabinoid levels in patients with motor degenerative disorders.

CONCLUSIONS:

The important role played by endocannabinoid system promises interesting developments, in particular to evaluate the effectiveness of new drugs in both psychiatry and neurology.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070159/

[The cannabinoid system and its importance in the perinatal period].

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“The cannabinoid system has been recently described, including the endogenous ligands, mainly arachidonic acid derivatives, and their specific receptors. Endocannabinoids are involved in the modulation of synaptic transmission, through which they exert their psychoactive, motor and antinociceptive effects, among others; they also exert extraneural effects, mainly immunomodulation and vasodilation.

Recent data suggest that the cannabinoid system might play an important role in human ontogeny and could participate in the implantation and early development of the embryo, in fetal brain development, and in the beginning of breast feeding after birth.

In addition, the vasodilatory effect of cannabinoids, together with inhibition of the release of excitotoxic amino acids and cytokines, as well as modulation of oxidative stress and the toxic production of nitric oxide, justify the growing evidence pointing to a possible neuroprotective effect of cannabinoids in perinatal asphyxia.”

http://www.ncbi.nlm.nih.gov/pubmed/16266619

Cannabinoids and Neuroprotection in Stroke

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“One of the most recently described neural signaling systems is that mediated by endogenous cannabinoids (endocannabinoids). Cannabinoids have recently been shown to attenuate neuronal injury induced by hypoxia and glucose deprivation in cell culture, as well as injury induced in rat brain following both global and focal cerebral ischemia in vivo.

Two endocannabinoids have been characterized in detail: N-arachidonylethanolamide and 2-arachidonylglycerol. Cannabinoid CB1 and CB2receptors have been cloned and an alternatively spliced CB1A isoform has been identified.

The development of metabolically stable, synthetic, enantiomeric cannabinoid receptor agonists and of CB1 and CB2 receptor antagonists has greatly aided the characterization of cannabinoid receptor-mediated processes, although certain aspects of cannabinoid signaling in some systems remain poorly understood.

Indirect evidence suggests that cannabinoids might serve as endogenous regulators of ischemic neuronal injury, but several recent reports provide more direct evidence bearing on such a role.

The author’s own findings provide evidence for CB1 receptor-mediated neuroprotection in vivo, but non-receptor-mediated protection in vitro.”

http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=3&p_RefId=129&p_IsPs=Y

Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease.

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“The impact of the endogenous cannabinoids (AEA, 2-AG, PEA, and virodamine) on the immune cell expressed cannabinoid receptors (CB1, CB2, TRPV-1, and GPR55) and consequent regulation of immune function is an exciting area of research with potential implications in the prevention and treatment of inflammatory and autoimmune diseases.

Despite significant advances in understanding the mechanisms through which cannabinoids regulate immune functions, not much is known about the role of endocannabinoids in the pathogenesis or prevention of autoimmune diseases.

Inasmuch as CB2 expression on immune cells and its role has been widely reported, the importance of CB1 in immunological disorders has often been overlooked especially because it is not highly expressed on naive immune cells.

Therefore, the current review aims at delineating the effect of endocannabinoids on CB1 receptors in T cell driven autoimmune diseases. This review will also highlight some autoimmune diseases in which there is evidence indicating a role for endocannabinoids in the regulation of autoimmune pathogenesis.

Overall, based on the evidence presented using the endocannabinoids, specifically AEA, we propose that the peripheral CB1 receptor is involved in the regulation and amelioration of inflammation associated with autoimmune diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/24911431

CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release.

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“Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability…

We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles.

These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.”

http://www.ncbi.nlm.nih.gov/pubmed/24089517

Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes.

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“Circulating levels of anandamide are increased in diabetes, and cannabidiol ameliorates a number of pathologies associated with diabetes. The aim of the present study was to examine how exposure to anandamide or cannabidiol might affect endothelial dysfunction associated with Zucker Diabetic Fatty rats…

These studies suggest that increased circulating endocannabinoids may alter vascular function both positively and negatively in type 2 diabetes, and that part of the beneficial effect of cannabidiol in diabetes may be due to improved endothelium-dependent vasorelaxation.”

http://www.ncbi.nlm.nih.gov/pubmed/24120371

A biosynthetic pathway for anandamide

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“The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released “on demand” by neurons in the brain. Anandamide is also generated by macrophages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE-PLD).

Here we document a biosynthetic pathway for anandamide in mouse brain…

Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC/phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target.

The observed exclusive role of the PLC/phosphatase pathway in LPS-induced AEA synthesis may offer therapeutic targets for the treatment of these conditions.

Furthermore, cannabinoids have immunosuppressive effects in autoimmune models of multiple sclerosis and diabetes, and mice deficient in CB1 receptors show increased susceptibility to neuronal damage found in autoimmune encephalitis…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557387/#!po=23.3333

Multiple sclerosis may disrupt endocannabinoid brain protection mechanism

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“Since the discovery of the endocannabinoids [eCB; anandamide and 2-arachidonoylglycerol (2-AG), various pathological conditions were shown to increase the eCB tone and to inhibit molecular mechanisms that are involved in the production, release, and diffusion of harmful mediators such as proinflammatory cytokines or excess glutamate.

In this issue of PNAS, Witting et al.  demonstrate that, unexpectedly and contrary to the effects of other brain diseases, cell damage induced by experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease widely used as a laboratory model of multiple sclerosis (MS), does not lead to enhancement of eCB levels, although the cannabinoid receptors remain functional.

Nearly two decades ago, Lyman et al.  reported that Δ9-THC, the psychoactive component of marijuana, suppresses the symptoms of EAE. A few years later, Wirguin et al. reported the same effect by Δ8-THC, a more stable and less psychotropic analogue of Δ9-THC.

Thus, THC was shown to inhibit both clinical and histological signs of EAE even before the endocannabinoids were described.

THC was also shown to control spasticity and tremor in chronic relapsing EAE, a further autoimmune model of MS , and to inhibit glutamate release via activation of the CB1-cannabinoid receptor in EAE. Moreover, mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration after immune attack in EAE.

Thus, the brain loses some of its endogenous neuroprotective capacity, but it may still respond to exogenous treatment with 2-AG or other CB1 agonists. Assuming that the biochemical changes taking place in the EAE model of MS are similar to those in MS itself, these results represent a biochemical-based support to the positive outcome noted with cannabinoid therapy in MS.

These data suggest that the high level of IFN-γ in the CNS, noted in mice with EAE, disrupts eCB-mediated neuroprotection, while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat MS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458835/

Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection

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“Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing from the original lesion site.

Evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds.

Indeed, activation of cannabinoid receptors reduces the production and diffusion of harmful mediators.

Here, we provide evidence that an exception to this pattern is found in experimental autoimmuneencephalomyelitis (EAE), a mouse model of multiple sclerosis…

Our data suggest that the high level of CNS IFN-gamma associated with EAE disrupts eCB-mediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458883/

Cannabinoid-induced autophagy regulates suppressor of cytokine signaling (SOCS)-3 in intestinal epithelium.

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“Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associates impaired autophagy, increased activity in the endocannabinoid system and upregulation of suppressor of cytokine signaling (SOCS)-3 protein expression during intestinal inflammatory states. We have investigated whether these three processes are linked. By assessing the impact of phyto-cannabinoid cannabidiol (CBD), synthetic cannabinoid (ACEA) and endocannabinoid (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated CaCo2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid receptor (CB)-1 mediated. In contrast, CBD was able to bypass both the CB1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking both early and late autophagy. In conclusion, the regulatory protein, SOCS3, is itself regulated by autophagy and cannabinoids play a role in this process, which could be important when considering therapeutic applications for the cannabinoids in inflammatory conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/24833710