Category Archives: Glaucoma

Involvement of cannabinoid receptor type 2 in light-induced degeneration of cells from mouse retinal cell line in vitro and mouse photoreceptors in vivo.

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Experimental Eye Research

“Earlier studies showed that the expressions of the agonists of the cannabinoid receptors are reduced in the vitreous humor of patients with age-related macular degeneration (AMD), and the cannabinoid type 2 receptor is present in the retinas of rats and monkeys. The purpose of this study was to determine whether the cannabinoid type 2 receptor is involved in the light-induced death of cultured 661W cells, an immortalized murine retinal cell line, and in the light-induced retinal degeneration in mice.

Time-dependent changes in the expression and location of retinal cannabinoid type 2 receptor were determined by Western blot and immunostaining. The cannabinoid type 2 receptor was down-regulated in murine retinae and cone cells. In the in vitro studies, HU-308, a cannabinoidtype 2 receptor agonist, had a protective effect on the light-induced death of 661W cells, and this effect was attenuated by SR144528, a cannabinoid type 2 receptor antagonist.

Because the cannabinoid type 2 receptor is a G-protein coupled receptor and is coupled with Gi/o protein, we investigated the effects of the cAMP-dependent protein kinase (PKA). HU-308 and H89, a PKA inhibitor, deactivated PKA in retinal cone cells, and H89 also suppressed light-induced cell death. For the in vivo studies, a cannabinoid type 2 receptor agonist, HU-308, or an antagonist, SR144528, was injected intravitreally into mouse eyes before the light exposure. Electroretinography was used to determine the physiological status of the retinas. Injection of HU-308 improved the a- and b-waves of the ERGs and also the thickness of the outer nuclear layer of the murine retina after light exposure.

These findings indicate that the cannabinoid type 2 receptor is involved in the light-induced retinal damage through PKA signaling. Thus, activation of cannabinoidtype 2 receptor may be a therapeutic approach for light-associated retinal diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29133122

http://www.sciencedirect.com/science/article/pii/S0014483516304456?via%3Dihub

[Cannabinoid receptor system regulates ion channels and synaptic transmission in retinal cells].

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“Endocannabinoid receptor system is extensively expressed in the vertebrate retina. There are two types of cannabinoid receptors, CB1 and CB2. Activation of these two receptors by endocannabinoids N-arachidonoylethanolamide (anandamine, AEA) and 2-arachidonyl glycerol (2-AG) regulates multiple neuronal and glial ion channels, thus getting involved in retinal visual information processing. In this review, incorporating our results, we discuss the modulation of cannabinoid CB1 and CB2 receptors on retinal neuronal and glial ion channels and retinal synaptic transmission.”

https://www.ncbi.nlm.nih.gov/pubmed/29063116

Activation of type 2 cannabinoid receptor (CB2R) by selective agonists regulates the deposition and remodelling of the extracellular matrix.

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“Remodelling of the extracellular matrix and accumulation of fibronectin and collagen type I play critical roles in scar formation following glaucoma filtration surgery. The transforming growth factor β1 (TGF-β1) signal transduction pathway is involved in this process in human Tenon’s fibroblasts (HTFs).

The type 2 cannabinoid receptor (CB2R) is an important member of the cannabinoidreceptor family of G protein-coupled receptors. In this study, we investigated the effects of the CB2R agonists HU308 and JWH133 on the deposition of newly formed extracellular matrix (ECM) and the contractility of HTFs.

CB2R was expressed in HTFs. Notably, the CB2R agonists HU308 and JWH133 ameliorated TGF-β1-induced generation of fibronectin, types I and III collagen, and the expression of matrix metalloproteinase 1 (MMP-1) and MMP-3. In addition, the CB2R agonists HU308 and JWH133 ameliorated TGF-β1-induced matrix contraction and remodelling in a dose- and time-dependent manner, respectively. HU308 and JWH133 also suppressed the TGF-β1-induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK).

Based on our results, agonistic activation of CB2R exerts a protective effect on scarring during the healing of wounds from glaucoma filtration surgery.”

https://www.ncbi.nlm.nih.gov/pubmed/28958132

Immunolocalization of cannabinoid receptor type 1 and CB2 cannabinoid receptors, and transient receptor potential vanilloid channels in pterygium.

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“Cannabinoids, as multi‑target mediators, activate cannabinoid receptors and transient receptor potential vanilloid (TRPV) channels. There is evidence to support a functional interaction of cannabinoid receptors and TRPV channels when they are coexpressed.

Human conjunctiva demonstrates widespread cannabinoid receptor type 1 (CB1), CB2 and TRPV channel localization. The aim of the present study was to investigate the expression profile for cannabinoid receptors (CB1 and CB2) and TRPV channels in pterygium, an ocular surface lesion originating from the conjunctiva.

The differentiated expression of cannabinoid receptors in combination with the presence of TRPV channels, in primary and recurrent pterygia, imply a potential role of these cannabinoidtargets in the underlying mechanisms of pterygium.”

 https://www.ncbi.nlm.nih.gov/pubmed/28849159
https://www.spandidos-publications.com/10.3892/mmr.2017.7246
“A pterygium is a pinkish, triangular tissue growth on the cornea of the eye.”  https://en.wikipedia.org/wiki/Pterygium_(conjunctiva)

Neuroprotection by (endo)cannabinoids in glaucoma and retinal neurodegenerative diseases.

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“Emerging neuroprotective strategies are being explored to preserve the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision.

Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina.

eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain.

Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28738764

http://www.eurekaselect.com/154386/article

The In Vivo Effects of the CB1-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice.

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“Orthosteric cannabinoid receptor 1 (CB1) activation leads to decreases in intraocular pressure (IOP).

The purpose of this study was to investigate the effects of the novel CB1-positive allosteric modulator (PAM) GAT229 on IOP.

The CB1 PAM GAT229 reduces IOP in ocular hypertensive mice and enhanced CB1-mediated IOP reduction when combined with subthreshold CB1 orthosteric ligands in normotensive mice. Administration of CB1 PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB1 activation.”

https://www.ncbi.nlm.nih.gov/pubmed/28719234

Medicinal Uses of Marijuana and Cannabinoids

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“In the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn’s disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.”

http://www.tandfonline.com/doi/abs/10.1080/07352689.2016.1265360?needAccess=true&journalCode=bpts20

“Review Identifies 140 Controlled Clinical Trials Related to Cannabis”  http://blog.norml.org/2017/06/04/review-identifies-140-controlled-clinical-trials-related-to-cannabis/

Rimonabant, a selective cannabinoid1 receptor antagonist, protects against light-induced retinal degeneration in vitro and in vivo.

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“The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer’s disease. An endogenous constellation of proteins related to cannabinoid1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid.

However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid1 receptor in light-induced retinal degeneration using in vitro and in vivo models.

Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer.

These results suggest that the cannabinoid1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28315677

Implication of cannabinoids in neurological diseases.

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“1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson’s disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/16699878

“Medical marijuana: emerging applications for the management of neurologic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/15458761

Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometry.

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“Cannabis has been used since ancient times to relieve neuropathic pain, to lower intraocular pressure, to increase appetite and finally to decrease nausea and vomiting.

The combination of the psychoactive cannabis alkaloid Δ9-tetrahydrocannabinol (THC) with the non-psychotropic alkaloids cannabidiol (CBD) and cannabinol (CBN) demonstrated a higher activity than THC alone.

Extraction efficiency of oil was significantly higher than that of water with respect to the different cannabinoids.

Fifteen minutes boiling was sufficient to achieve the highest concentrations of cannabinoids in the cannabis tea solutions.

As the first and most important aim of the different cannabis preparations is to guarantee therapeutic continuity in treated individuals, a strictly standardized preparation protocol is necessary to assure the availability of a homogeneous product of defined stability.”

https://www.ncbi.nlm.nih.gov/pubmed/28207408