Tag Archives: endocannabinoids

Role of cannabinoids and endocannabinoids in cerebral ischemia

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“The human costs of stroke are very large and growing; it is the third largest cause of death in the United States and survivors are often faced with loss of ability to function independently. There is a large need for therapeutic approaches that act to protect neurons from the injury produced by ischemia and reperfusion… 

 Overall, the available data suggest that inhibition of CB1 receptor activation together with increased CB2 receptor activation produces beneficial effects.

These studies support the hypothesis that activation of the CB1 receptor by highly efficacious, exogenous agonists during the acute phase of ischemia decreases the likelihood of the occurrence of a detrimental event at the time of ischemia and thereby reduces the amount of infarction and neuronal death long-term… A protective role of the CB1 receptor is also supported by studies…

While it is possible that the ECS will be added to the long list of neuroprotective agents that show promise in animals and do not work in humans, there are a few reasons to be optimistic about this class of drugs. First, many of the other agents did not work because they do not cross the blood brain barrier. While the considerable lipophilicity of the cannabinoids poses its own set of problems, these drugs have no problems entering the brain. Second, the ECS is multifactorial and could “cover” multiple biochemical pathways in a single drug. Third, manipulations of the ECS has been shown to be beneficial in several preclinical models. Only time and further research will answer the most important question, are the cannabinoids of therapeutic benefit in humans suffering from stroke?”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581413/

 

Endocannabinoids and cannabinoid receptors in ischaemia–reperfusion injury and preconditioning

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“This review is aimed to discuss the role of endocannabinoids and CB receptors in various forms of I/R injury (myocardial, cerebral, hepatic and circulatory shock) and preconditioning, and to delineate the evidence supporting the therapeutic utility of selective CB2 receptor agonists, which are devoid of psychoactive effects, as a promising new approach to limit I/R-induced tissue damage.

In this review, we will discuss the triggers and sources of endocannabinoid production during various forms of I/R injury (myocardial, cerebral, hepatic and retinal ischaemia, and circulatory shock) and preconditioning, as well as the diverse role of these novel mediators and their receptors in these processes. We will also overview the accumulating evidence obtained through the use of various synthetic CB1/CB2 receptor ligands, with particular focus on the novel role of CB2 receptors, suggesting that the modulation of the endocannabinoid system can be therapeutically exploited in various forms of I/R injury.

Cerebral I/R (stroke)

The first evidence for the neuroprotective effect of CBs came from the stroke research field from studies using synthetic non-psychotropic CB Dexanabinol/HU-211, which exerted its beneficial effects through CB1/CB2-independent mechanisms.

Collectively, it appears that both CB1 agonists and antagonists may afford neuroprotective effects against cerebral I/R…

There is considerable interest in the development of selective CB2 receptor agonists, which are devoid of psychoactive properties of CB1 agonists, for various inflammatory disorders. Further studies should also establish the therapeutic window of protection during the reperfusion phase with the currently available CB2 receptor agonists, and new compounds should also be designed with better in vivo bioavailability, to devise clinically relevant treatment strategies against various forms of I/R. Nevertheless, the recently observed beneficial effects of CB2 receptor agonists in hepatic and other forms of I/R, coupled with the absence of psychoactive properties, and antifibrotic effects of CB2 receptor in the liver suggest that this approach may represent a novel promising strategy against various forms of I/R injury and other inflammatory disorders.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219536/

Increased Severity of Stroke in CB1 Cannabinoid Receptor Knock-Out Mice

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“These findings indicate that endogenous cannabinoid signaling pathways protect mice from ischemic stroke by a mechanism that involves CB1 receptors, and suggest that both blood vessels and neurons may be targets of this protective effect.

 Endogenous cannabinoid signaling pathways have been implicated in protection of the brain from hypoxia, ischemia, and trauma…

Cannabinoids, which include the marijuana constituent Δ9-tetrahydrocannabinol and endogenous cannabinoids (endocannabinoids) produced in the brain, exert many of their effects through the G-protein-coupled CB1 receptor.

Cannabinoids reduce neuronal death from a variety of insults, including excitotoxicity, oxidative stress, hypoxia, ischemic stroke and trauma…

Clinical stroke, which usually results from cerebral ischemia, is a common and frequently incapacitating problem for which satisfactory treatment is generally unavailable. Identifying new endogenous systems that mitigate ischemic brain injury through effects on neurons, blood vessels, or both (such as the endocannabinoid signaling pathway) may help to guide the search for improved therapies.”

Full text: http://www.jneurosci.org/content/22/22/9771.long

Endocannabinoids and obesity.

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“A safe and effective antiobesity drug is needed to combat the global obesity epidemic. The discovery of cannabinoids from medicinal herbs has revealed the endocannabinoid system (ECS) in animals and humans, which regulates various physiological activities such as feeding, thermogenesis, and body weight (BW).

Although cannabinoid receptors 1 (CB1) antagonists have shown antiobesity efficacies in animal models and in the clinic, they failed to establish as a treatment due to their psychological side effects.

 Recent studies indicate that CB1 in various peripheral tissues may mediate some of the therapeutic effects of CB1 antagonists, such as improved lipid and glucose homeostasis.

 It rationalizes the development of compounds with limited brain penetration, for minimizing the side effects while retaining the therapeutic efficacies. A survey of the literature has revealed some controversies about how the ECS affects obesity. This review summarizes the research progresses and discusses some future perspectives.”

http://www.ncbi.nlm.nih.gov/pubmed/23374723

Revisiting CB1 receptor as drug target in human melanoma.

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“Previous studies have indicated the antitumoral effect of human melanocytes, human melanoma cell lines expressing CB1 receptor (CB1), and of the peritumoral administration of endocannabinoids. In the present study, we systematically screened several human melanoma cell lines for the expression of CNR1 and demonstrated transcription of the authentic gene. The product of CNR1, the CB1 protein, was found localized to the cell membrane as well as to the cytoskeleton. Further, the studied human melanoma cell lines expressed functional CB1 since physiological and synthetic ligands, anandamide (AEA), Met-F-AEA, ACEA and AM251 showed a wide range of biological effects in vitro, for example anti-proliferative, proapoptotic and anti-migratory. More importantly, our studies revealed that systemic administration of a stable CB1 agonist, ACEA, into SCID mice specifically inhibited liver colonization of human melanoma cells.

Since therapeutic options for melanoma patients are still very limited, the endocannabinoid-CB1 receptor system may offer a novel target.”

http://www.ncbi.nlm.nih.gov/pubmed/22447182

Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect.

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“Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system.

We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors… 

Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells.

Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis.

The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/21298280

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.

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“The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated…

CONCLUSIONS:

This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors.

This may contribute to the improvement of long-term palliation or cure of melanoma.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364151/

The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi’s sarcoma cells in vitro.

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“Kaposi’s sarcoma is a highly vascularized mesenchymal neoplasm arising with multiple lesions of the skin. Endogenous cannabinoids have been shown to inhibit proliferation of a wide spectrum of tumor cells. We studied the effects of cannabinoids on human Kaposi’s sarcoma cell proliferation in vitro.

 To do so, we first investigated the presence of the cannabinoid receptors CB(1) and CB(2) mRNAs in the human Kaposi’s sarcoma cell line KS-IMM by RT-PCR and, subsequently, the effects of the mixed CB(1)/CB(2) agonist WIN-55,212-2 (WIN) on cell proliferation in vitro. WIN showed antimitogenic effects on Kaposi’s sarcoma cells…

  In view of the antiproliferative effects of cannabinoids on KS-IMM cells, one could envision the cannabinoid system as a potential target for pharmacological treatment of Kaposi’s sarcoma”

http://www.ncbi.nlm.nih.gov/pubmed/19539619

The role of the pancreatic endocannabinoid system in glucose metabolism.

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“The endogenous cannabinoid system participates in the regulation of energy homeostasis, and this fact led to the identification of a new group of therapeutic agents for complicated obesity and diabetes. Cannabinoid receptor antagonists are now realities in clinical practice. The use of such antagonists for reducing body weight gain, lowering cholesterol and improving glucose homeostasis is based on the ability of the endocannabinoids to coordinately regulate energy homeostasis by interacting with central and peripheral targets, including adipose tissue, muscle, liver and endocrine pancreas. In this review we will analyse the presence of this system in the main cell types of the islets of Langerhans, as well as the physiological relevance of the endocannabinoids and parent acylethanolamides in hormone secretion and glucose homeostasis. We will also analyse the impact that these findings may have in clinical practice and the potential outcome of new therapeutic strategies for modulating glucose homeostasis and insulin/glucagon secretion.”

http://www.ncbi.nlm.nih.gov/pubmed/19285263

Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia.

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“Cannabinoid CB(1) receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake.

The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells.

Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured.

RESULTS:

Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB(1) receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose.

CONCLUSIONS:

Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.”

http://jcem.endojournals.org/content/91/8/3171.long