Tag Archives: therapeutic

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type-2 Diabetes.

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“Islet inflammation promotes β-cell loss and type-2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets.

Here, we analyzed CB1R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates.

Adoptive transfer of CB1R-/- bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy. ZDF islets contain elevated levels of CB1R, IL-1β, TNF-α, the chemokine CCL2 and interferon regulatory factor-5 (IRF5), a marker of M1 inflammatory macrophage polarization.

In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα-dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia.

Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/28082458

Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

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“Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/25504799

Development of new inhibitors for N-acylethanolamine-hydrolyzing acid amidase as promising tool against bladder cancer.

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“The endocannabinoid system is a signaling system involved in a wide range of biological effects.

Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits.

Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control.

Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines.

These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition.

Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/28062195

[Possibilities of applying cannabinoids’ in the treatment of glaucoma].

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“Over a period of several decades numerous scientific research has proven that, regardless of the route of administration, cannabinoids are able to decrease intraocular pressure.

What is more, these compounds are characterized by neuroprotection and vasodilatation properties, that additionally substantiate it’s therapeutic utility in conservative treatment of glaucoma.

So far, it has not been described in details what mechanism is used to lower the intraocular pressure by cannabinoids. Nevertheless, the presence of endocannabinoid receptors in structures of the eye responsible for formation and outflow of aqueous humor is an explanation for effectiveness of these compounds, when administered in topical form.

These days, with the aid of modern pharmacological technology are available significantly bigger possibilities of improving bioavailability of cannabinoids administered to the eye than in the past, as well as limitation of it’s undesired side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/19112869

Soft cannabinoid analogues as potential anti-glaucoma agents.

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“Cannabinoids have intraocular pressure (IOP) lowering effects, thus, they have a therapeutic potential in the treatment of glaucoma.

Our aim was to develop a safer, cannabinoid type anti-glaucoma agent, a topically applied soft analogue, that has local, but no systemic effect.

The lead compound chosen was a nitrogen-containing cannabinoid analogue that was shown to have IOP lowering activity.

A full library of possible soft drugs was generated and the structures were ranked based on the closeness of calculated properties to those of the lead compound.

The lead compound has been synthesized, and a preliminary pharmacological study was performed.

The structure-activity relationship and pharmacological results indicate a good possibility for the development of a safe, soft anti-glaucoma agent.”

https://www.ncbi.nlm.nih.gov/pubmed/10756540

Cannabinoids in the treatment of glaucoma.

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“The leading cause of irreversible blindness is glaucoma, a disease normally characterized by the development of ocular hypertension and consequent damage to the optic nerve at its point of retinal attachment. This results in a narrowing of the visual field, and eventually results in blindness.

A number of drugs are available to lower intraocular pressure (IOP), but, occasionally, they are ineffective or have intolerable side-effects for some patients and can lose efficacy with chronic administration.

The smoking of marijuana has decreased IOP in glaucoma patients. Cannabinoid drugs, therefore, are thought to have significant potential for pharmaceutical development.

The discovery of ocular cannabinoid receptors implied an explanation for the induction of hypotension by topical cannabinoid applications, and has stimulated a new phase of ophthalmic cannabinoid research.

Featured within these investigations is the possibility that at least some cannabinoids may ameliorate optic neuronal damage through suppression of N-methyl-D-aspartate receptor hyperexcitability, stimulation of neural microcirculation, and the suppression of both apoptosis and damaging free radical reactions, among other mechanisms.

Separation of therapeutic actions from side-effects now seems possible through a diverse array of novel chemical, pharmacological, and formulation strategies.”

 https://www.ncbi.nlm.nih.gov/pubmed/12182967

[Cannabinoid applications in glaucoma].

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“Glaucoma is a slowly progressive optic neuropathy that is one of the leading causes of legal blindness throughout the world.

Currently there is a limited group of topical drugs for the medical treatment of glaucoma is currently limited, and research needs to be focused on new therapeutic horizons, such as the potential usefulness of the cannabinoid agonists for the treatment of glaucoma.

To review the current scientific literature related to the beneficial effects derived from the different ways of administration of cannabinoids indicated for the glaucomatous optic neuropathy.

Cannabinoid receptors have shown an intense expression in ocular tissues implicated in the regulation of the intraocular pressure, as well as inner layers of the retina. Through activation of CB1 and CB1 specific receptors and through other still unknown pathways, the cannabinoid agonists have shown both a clear hypotensive, as well as an experimentally proved neuroprotective effect on retinal ganglion cells.

CONCLUSIONS:

Some cannabinoid agonists (WIN 55212-2, anandamide) have demonstrated, in experimental studies, to act as «ideal drugs» in the management of glaucoma, as they have been shown to have good tolerability after topical application, efficiently reduce intraocular pressure, and behave as neuroprotectors on retinal ganglion cells.”

https://www.ncbi.nlm.nih.gov/pubmed/21414525

Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P

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“Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis).

Neural control of colon motility is profoundly altered in patients with diverticulitis. Their raised levels of anandamide, apparent desensitisation of the presynaptic neural cannabinoid CB1 receptor, and the SR141716 induced intrinsic response, suggest that endocannabinoids may be involved in the pathophysiology of complications of colonic diverticular disease.

Agents acting on the endocannabinoid system could eventually find therapeutic application in colonic inflammatory and motility disorders.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856307/

Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1β (IL-1β) signalling.

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“Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis.

Activation of cannabinoid receptors suppresses chronic inflammatory responses through the attenuation of pro-inflammatory mediators. Moreover, the endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous system).

The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1β (interleukin-1β) associated signalling pathways and NSC biology, in order to develop therapeutical strategies on CNS diseases that may facilitate brain repair.

NSCs express functional CB1 and CB2 cannabinoid receptors, DAGLα (diacylglycerol lipase α) and the NSC markers SOX-2 and nestin. We have investigated the role of CB1 and CB2 cannabinoid receptors in the control of NSC proliferation and in the release of immunomodulators [IL-1β and IL-1Ra (IL-1 receptor antagonist)] that control NSC fate decisions. Pharmacological blockade of CB1 and/or CB2 cannabinoid receptors abolish or decrease NSC proliferation, indicating a critical role for both CB1 and CB2 receptors in the proliferation of NSC via IL-1 signalling pathways.

Thus the endocannabinoid system, which has neuroprotective and immunomodulatory actions mediated by IL-1 signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult NSCs, and this may be of therapeutic interest in the emerging field of brain repair.

In summary, cannabinoids and IL-1β seem to play antagonistic roles in neurogenesis: although cannabinoids increase proliferation and induce formation and maturation of new neurons, IL-1β blocks proliferation and formation of new neurons, inducing a shift towards a glial fate. This may be important in situations such as in aging, neurodegenerative diseases, and lesions of the brain and spinal cord.”

http://www.biochemsoctrans.org/content/41/6/1577.long

Diuretic effects of cannabinoids.

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“These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.

Overall, our data indicate that diuresis is a CB1-mediated effect that may serve as a reliable and objective physiologic measure of cannabinoid action in rats; the circumstances under which these results represent a potential therapeutic benefit or potential liability of cannabinoids remain to be determined.

The implications of these findings currently are poorly understood, although a better understanding of mechanisms and sites of action by which cannabinoids increase urine loss may lead to the rational development of novel cannabinergic medications.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533417/

“Diuretics are medicines that help reduce the amount of water in the body. Diuretics are used to treat the buildup of excess fluid in the body that occurs with some medical conditions such ascongestive heart failure, liver disease, and kidney disease. Some diuretics are also prescribed to treat high bloodpressure. These drugs act on the kidneys to increase urine output. This reduces the amount of fluid in the bloodstream,which in turn lowers blood pressure.” http://medical-dictionary.thefreedictionary.com/diuretics