Category Archives: Endocannabinoid System

Modulation of The Balance Between Cannabinoid CB1 and CB2 Receptor Activation During Cerebral Ischemic/Reperfusion Injury

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“A number of investigations have shown that CB2 receptor activation has anti-inflammatory therapeutic potential in various CNS diseases, such as multiple sclerosis, traumatic brain injury and Alzheimer’s disease. Because inflammatory responses have been shown to be important contributors to secondary injury following cerebral ischemia; the CB2 receptor has been investigated as a potential therapeutic target in stroke…

The most striking changes were obtained by combing a CB1 antagonist with a CB2 agonist. This combination elevated the cerebral blood flow during ischemia and reduced infarction by 75%…during cerebral ischemia/reperfusion injury, inhibition of CB1 receptor activation is protective while inhibition of CB2 receptor activation is detrimental.

 The greatest degree of neuroprotection was obtained by combining an inhibitor of CB1 activation with an exogenous CB2 agonist.

In conclusion, the results of this investigation demonstrate dynamic changes in the expression of CB1 and CB2 receptors during cerebral ischemic/reperfusion injury in mice. The effects of stimulation of these receptors on damage ischemia/reperfusion injury differed dramatically. Stimulation of the CB2 receptor was found to be neuroprotective, while inhibition of the CB1 receptor was also protective,too. The combination of a CB2 agonist and a CB1 antagonist provided the greatest degree of protection and indicated a synergistic effect derived from combining these agents. Therefore, changing the balance of stimulation of these receptors by endogenous cannabinoids may provide an important therapeutic strategy during stroke.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577828/

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/

 

Endocannabinoid regulation of matrix metalloproteinases: implications in ischemic stroke.

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“Stroke is a major cause of morbidity and mortality and follows heart disease and cancer as the third leading cause of death in Western societies. Despite many advances in stroke research and pharmacotherapy, clinical treatment of this debilitating disorder is still inadequate.

Recent findings from several laboratories have identified the endocannabinoid signaling pathway, comprised of the endocannabinoid agonist anandamide and its pharmacological targets, CB1 and CB2 cannabinoid receptors and associated anandamide receptors, as a physiological system with capacity to mitigate cardiovascular and cerebrovascular disorders through neuronal and endothelial actions. Variability in experimental stroke models and modes of outcome evaluation, however, have provoked controversy regarding the precise roles of endocannabinoid signals in mediating neural and/or vascular protection versus neurovascular damage.

Clinical trials of the CB1 antagonist rimonabant demonstrate that modulation of endocannabinoid signaling during metabolic regulation of vascular disorders can significantly impact clinical outcomes, thus providing strong argument for therapeutic utility of endocannabinoids and/or cannabinoid receptors as targets for therapeutic intervention in cases of stroke and associated vascular disorders.

The purpose of this review is to provide updated information from basic science and clinical perspectives on endocannabinoid ligands and their effects in the pathophysiologic genesis of stroke. Particular emphasis will be placed on the endocannabinoids anandamide and 2-arachidonylglycerol and CB1 receptor-mediated mechanisms in the neurovascular unit during stroke pathogenesis. Deficiencies in our knowledge of endocannabinoids in the etiology and pathogenesis of stroke, caveats and limitations of existing studies, and future directions for investigation will be addressed.”

http://www.ncbi.nlm.nih.gov/pubmed/17979695

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/

CB1 cannabinoid receptor induction in experimental stroke.

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“Cannabinoids protect cortical neurons from ischemic injury by interacting with CB1 receptors. Because a variety of neuroprotective genes are induced in cerebral ischemia, we examined the effect of experimental stroke, produced by 20 minutes of middle cerebral artery occlusion in rats, on CB1 receptor expression.

Western blotting and immunohistochemistry showed that CB1 expression on neurons was increased in the arterial boundary zone of the cortical mantle, beginning by 2 hours and persisting for 72 hours or more after ischemia.

These findings are consistent with a neuroprotective role for endogenous cannabinoid signaling pathways and with a potential therapeutic role in stroke for drugs that activate CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/10939579

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

The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities

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“The endocannabinoid system (ECS) and the skin. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes. It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

Perspectives in the ECS-targeted management of skin diseases

… preclinical data encourage one to systematically explore whether ECS-modulating drugs can be exploited in the management of common skin disorders…

 … we review preliminary data and discuss the possible applications of ECS-targeted therapies…ECS-targeted approaches in skin diseases. Modulations of the fine-tuned tone of the cutaneous endocannabinoid system (ECS) could have therapeutic values in the management of a large variety of human skin diseases…

Conclusions and future directions in experimental and clinical research

… it is envisaged (this is also strongly supported by pilot studies) that the targeted manipulation of the ECS might be beneficial in a multitude of human skin diseases. However, to predict the real therapeutic potential and translate the exciting preclinical observations discussed earlier into clinical practice, numerous important questions should carefully be addressed. Nevertheless, targeting the cutaneous ECS for therapeutic gain remains an intriguing and provocative possibility warranting future studies.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

The Cannabinoid Receptors are Required for UV-Induced Inflammation and Skin Cancer Development

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“Solar ultraviolet (UV) irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates the cannabinoid receptors 1 and 2 (CB1/2)…

These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development…

Manipulation of the cannabinoid receptors has been useful in the management of pain, treatment of osteoporosis, inflammation, and cancer…”

.Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390870/