Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia.

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“Retinal ischemia is a pathological event present in several retinopathies such as diabetic retinopathy and glaucoma, leading to partial or full blindness with no effective treatment available.

Since synthetic and endogenous cannabinoids have been studied as modulators of ischemic events in the central nervous system (CNS), the present study aimed to investigate the involvement of cannabinoid system in the cell death induced by ischemia in an avascular (chick) retina.

We observed that chick retinal treatment with a combination of WIN 55212-2 and cannabinoid receptor antagonists (either AM251/O-2050 or AM630) decreased the release of lactate dehydrogenase (LDH) induced by retinal ischemia in an oxygen and glucose deprivation (OGD) model.

Further, the increased availability of endocannabinoids together with cannabinoid receptor antagonists also had a neuroprotective effect.

Surprisingly, retinal exposure to any of these drugs alone did not prevent the release of LDH stimulated by OGD.

Since cannabinoids may also activate transient receptor potential (TRP) channels, we investigated the involvement of TRPA1 receptors (TRPA1) in retinal cell death induced by ischemic events.

We demonstrated the presence of TRPA1 in the chick retina, and observed an increase in TRPA1 content after OGD, both by western blot and immunohistochemistry.

In addition, the selective activation of TRPA1 by mustard oil (MO) did not worsen retinal LDH release induced by OGD, whereas the blockage of TRPA1 completely prevented the extravasation of cellular LDH in ischemic condition.

Hence, these results show that during the ischemic event there is an augment of TRPA1, and activation of this receptor is important in cell death induction.

The data also indicate that metabotropic cannabinoid receptors, both type 1 and 2, are not involved with the cell death found in the early stages of ischemia. Therefore, the study points to a potential role of TRPA1 as a target for neuroprotective approaches in retinal ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/27876485

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Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia

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“Although cannabinoids have been used for millennia for treating pain and other symptoms, their mechanisms of action remain obscure.

With the heralded identification of multiple G-protein-coupled receptors (GPCRs) mediating cannabinoid effects nearly two decades ago, the mystery of cannabinoid pharmacology was thought to be solved…

Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown.

Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1.

Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models.

Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863326/

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The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis.

“The non-psychotropic cannabinoid¬†cannabichromene¬†is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis…

CONCLUSION AND IMPLICATIONS:

Cannabichromene¬†exerts anti-inflammatory actions in activated macrophages – with tonic CB1 cannabinoid signalling being negatively coupled to this effect – and ameliorates experimental murine colitis.”

http://www.ncbi.nlm.nih.gov/pubmed/23373571

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Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice.

“BACKGROUND AND PURPOSE:

Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.”

“CONCLUSION AND IMPLICATIONS:

CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.”

http://www.ncbi.nlm.nih.gov/pubmed/22300105

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