Tag Archives: Cannabinoids

Inhibition of endocannabinoid degradation in experimental endotoxemia reduces leukocyte adhesion and improves capillary perfusion in the gut.

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“Changes in leukocyte-endothelial and microvascular perfusion are hallmark events in inflammation. Thus, protection of the intestinal microcirculation represents a pivotal therapeutic target in systemic inflammation and sepsis.

The endocannabinoid system (ECS) modulates a number of critical homeostatic functions and has been associated with anti-inflammatory responses. Our study aimed to examine intestinal leukocyte adhesion and capillary perfusion following selective inhibition of the endocannabinoid degradation enzyme, fatty acid amide hydrolase (FAAH), in experimental sepsis (endotoxemia).

Conclusions: FAAH inhibition prevents the LPS-induced increase in leukocyte adhesion and improves the capillary perfusion of the gut. This might be mediated in part by CB2R activation.

Our study encourages further investigation into the therapeutic potential of drugs targeting the ECS in sepsis.”

More: http://www.ncbi.nlm.nih.gov/pubmed/23382309

Update on the Role of Cannabinoid Receptors after Ischemic Stroke

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“The endocannabinoid system is considered as a major modulator of the cerebral blood flow, neuroinflammation, and neuronal survival… Evidence from animal models and in vitro studies suggests a global protective role for cannabinoid receptors agonists in ischemic stroke…Given its potent anti-inflammatory activities on circulating leukocytes, the CB2 activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke…

Synthetic cannabinoids have been also investigated in animal models showing an improvement of the ischemic injury in the liver, heart, and brain. Furthermore, phytocannabinoids have been also isolated from the Cannabis sativa. Since this plant contains about 80 different cannabinoids, a strong work is still needed to test all these active compounds. This delay in cannabinoid research might be also due to the very low dose of certain cannabinoids in the plant. Thus, since Δ9-tetrahydrocannabidiol (THC) and cannabidiol (CBD) represent up to 40% of the total cannabinoid mass, these compounds have been considered as the most active mediators…

The encouraging therapeutic results of this study are in partial contrast with previous case reports, suggesting a potential relationship between stroke and chronic cannabis abuse in young human beings…

We believe that the “cannabinoid” approach represents an interesting therapeutic strategy still requiring further validations to improve neurologic and inflammatory outcomes in ischemic stroke.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337695/

Modulation of Cannabinoid Receptor Activation as a Neuroprotective Strategy for EAE and Stroke

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“These results provide evidence that alteration of the activation patterns of the various cannabinoid receptors warrant consideration for future therapeutic strategies.

Interest in the medicinal use of Cannabis sativa (marijuana) has a long historical record, extending back thousands of years. In comparison to the extensive history for medicinal applications of marijuana, the existence of an “endocannabinoid system”, with important homeostatic and pathologic functions, has only recently gained appreciation. The endocannabinoid system consists of endogenously produced cannabinoids, their receptors, and the enzymes responsible for their synthesis and degradation…

Although used in ancient Greece, Rome, and China for therapeutic purposes, concern about the use of cannabinoids as a drug of abuse has dampened interest in developing the potential therapeutic benefits of these compounds. However, a better understanding of the biologic effects has led recently to an upsurge in interest for the development of therapeutic drugs through modification of the endocannabinoid system. An additional incentive was provided by the development of synthetic cannabinoid analogs and specific inhibitors of cannabinoid receptors. Several excellent reviews cover the therapeutic potential of cannabinoids….

The present review is focused on the effects of CB2 receptor activation in models of multiple sclerosis (experimental autoimmune encephalomyelitis) and stroke (middle cerebral occlusion/reperfusion).

In summary, selective CB2 receptor agonists and CB1 receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855650/

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/

 

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

Cannabinoid receptors as novel targets for the treatment of melanoma

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“Melanoma causes the greatest number of skin cancer-related deaths worldwide. Here, we evaluated the efficacy of cannabinoid receptor agonists, a new family of potential antitumoral compounds, at skin melanoma. Human melanomas and melanoma cell lines express CB1 and CB2 cannabinoid receptors. Activation of these receptors decreased growth, proliferation, angiogenesis and metastasis, and increased apoptosis, of melanomas in mice. Cannabinoid antimelanoma activity was independent of the immune status of the animal, could be achieved without overt psychoactive effects and was selective for melanoma cells vs. normal melanocytes.

Cannabinoid antiproliferative action on melanoma cells…

 These findings may contribute to the design of new chemotherapeutic strategies for the management of melanoma.

 …the present report, together with the implication of CB2 receptors in the control of processes such as pain initiation, emesis, and inflammation, opens the attractive possibility of finding cannabinoid-based therapeutic strategies devoid of nondesired psychotropic side effects.

Specifically, the antiproliferative effect of cannabinoids reported here may set the basis for a new therapeutic approach for the treatment of malignant melanoma.”

Full text: http://www.fasebj.org/content/20/14/2633.long