Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection.

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“Recent evidence shows that the endocannabinoid system is involved in the pathogenesis of numerous neurodegenerative diseases of the central nervous system. Pharmacologic modulation of cannabinoid receptors or the enzymes involved in the synthesis, transport, or breakdown of endogenous cannabinoids has proved to be a valid alternative to conventional treatment of these diseases.

In this review, we will examine recent findings that demonstrate the involvement of the endocannabinoid system in glaucoma, a major neurodegenerative disease of the eye that is a frequent cause of blindness.

Experimental findings indicate that the endocannabinoid system contributes to the control of intraocular pressure (IOP), by modulating both production and drainage of aqueous humor.

There is also a growing body of evidence of the involvement of this system in mechanisms leading to the death of retinal ganglion cells, which is the end result of glaucoma.

Molecules capable of interfering with the ocular endocannabinoid system could offer valid alternatives to the treatment of this disease, based not only on the reduction of IOP but also on neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/18929127

[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.”

[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

The arguments for and against cannabinoids application in glaucomatous retinopathy.

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“Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder.

Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma.

Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye.

In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature.

In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed.”

https://www.ncbi.nlm.nih.gov/pubmed/28027538

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.

 

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“The diurnal cycling of intraocular pressure (IOP) was first described in humans more than a century ago. This cycling is preserved in other species. The physiologic underpinning of this diurnal variation in IOP remains a mystery, even though elevated pressure is indicated in most forms of glaucoma, a common cause of blindness. Once identified, the system that underlies diurnal variation would represent a natural target for therapeutic intervention.

We now report that NAPE-PLD and FAAH mice do not exhibit a diurnal cycling of IOP. These enzymes produce and break down acylethanolamines, including the endogenous cannabinoid anandamide. The diurnal lipid profile in mice shows that levels of most N-acyl ethanolamines and, intriguingly, N-arachidonoyl glycine (NAGly), decline at night: NAGly is a metabolite of arachidonoyl ethanolamine and a potent agonist at GPR18 that lowers intraocular pressure. The GPR18 blocker O1918 raises IOP during the day when pressure is low, but not at night. Quantitative PCR analysis shows that FAAH mRNA levels rise with pressure, suggesting that FAAH mediates the changes in pressure.

 

CONCLUSIONS:

Our results support FAAH-dependent NAGly action at GPR18 as the physiologic basis of the diurnal variation of intraocular pressure in mice.”

https://www.ncbi.nlm.nih.gov/pubmed/27893106

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

Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

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“Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death.

The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS).

These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.”

Cannabis improves night vision: a case study of dark adaptometry and scotopic sensitivity in kif smokers of the Rif mountains of northern Morocco.

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“Previous reports have documented an improvement in night vision among Jamaican fishermen after ingestion of a crude tincture of herbal cannabis, while two members of this group noted that Moroccan fishermen and mountain dwellers observe an analogous improvement after smoking kif, sifted Cannabis sativa mixed with tobacco (Nicotiana rustica).

Field-testing of night vision has become possible with a portable device, the LKC Technologies Scotopic Sensitivity Tester-1 (SST-1).

This study examines the results of double-blinded graduated THC administration 0-20 mg (as Marinol) versus placebo in one subject on measures of dark adaptometry and scotopic sensitivity.  Analogous field studies were performed in Morocco with the SST-1 in three subjects before and after smoking kif.

In both test situations, improvements in night vision measures were noted after THC or cannabis. It is believed that this effect is dose-dependent and cannabinoid-mediated at the retinal level.

Further testing may assess possible clinical application of these results in retinitis pigmentosa or other conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/15182912