Yousuf M. Khalifa

Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor.

PURPOSE Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD. METHODS The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined. RESULTS The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosines TNF-alpha suppression after treatment with LPS. CONCLUSIONS These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBDs anti-inflammatory effects are linked to the inhibition of adenosine uptake.

Neuroprotective and Intraocular Pressure-Lowering Effects of (–)Δ9-Tetrahydrocannabinol in a Rat Model of Glaucoma

In glaucoma, retinal ganglion cell (RGC) death is induced by many risk factors, including ocular hypertension. It has been proposed that glutamate-mediated oxidative stress may also contribute to this RGC death. Cannabinoids are known to possess therapeutic properties including ocular hypotension and antioxidation. In this study, we test the hypothesis that (–)Δ9-tetrahydrocannabinol (THC) lowers intraocular pressure (IOP) and prevents RGC death in a rat model of glaucoma. Arat model of experimental glaucoma with chronic, moderately elevated IOP was produced unilaterally by cauterization of episcleral vessels. Rats received weekly injections of THC at a level of 5 mg/kg or vehicle for 20 weeks. IOP of both eyes was measured weekly on anesthetized animals immediately before THC treatment. RGCs were labeled in a retrograde fashion and counted in whole-mounted retinas. IOP was elevated in all operated eyes 1 day after the operation and remained elevated in the vehicle-treated rats throughout 20 weeks. In THC-treated rats, IOP elevation in operated eyes was diminished 2 weeks after operation and remained reduced. IOP in the contralateral control eyes was not affected by THC. In the operated eyes of vehicle-treated animals, there was a loss of ∼50 and 40% of the RGCs in the peripheral and central retina, respectively. The RGC loss in the operated eyes of the THC-treated animals was reduced to 10–20%. These results demonstrate that THC is a neuroprotectant that preserves RGCs in an experimental model of glaucoma, possibly through a reduction in IOP.

Temporalis Fascia in the Management of Gold Eyelid Weight Extrusion

A patient with a traumatic facial nerve palsy and resulting paralytic lagophthalmos underwent surgical implantation of a gold weight load, which extruded 4 weeks after surgery. Cicatricial contraction of the anterior lamella developed, and a full-thickness skin graft was used to correct the cicatrix. A second gold weight loading procedure was then undertaken with a temporalis fascia drape added to reduce the risk of extrusion. One year after surgery, there is no sign of migration or extrusion. Gold weight loading has emerged as the standard in management of paralytic lagophthalmos, with extrusion cited as the most serious complication. We propose temporalis fascia draping as an adjuvant procedure in the reimplantation of an extruded gold weight.

Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development

Diabetic retinopathy is a leading cause of blindness in the Western world. However, treatment options for diabetic retinopathy are limited and display poor efficacy with marked patient-to-patient variation in therapeutic outcomes. Discovery of new molecular entities acting on mechanistically novel biological pathways remains as one of the key research priorities in diabetic retinopathy. Moreover, given the variable success of the existing treatment modalities, a targeted and personalized drug development strategy could be more fruitful for rational and successful transition of preclinical discoveries to the clinical realm. This review is focused on cannabidiol, a non-psychoactive native cannabinoid, as an emerging and novel therapeutic modality based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy - one of the retinal diseases associated with vascular neuroinflammation. We present the postulated and preclinically documented novel mechanisms that may underlie cannabidiol mode of action in diabetic retinopathy. We discuss the interindividual variation in pharmacokinetic pathways as well as in the SLC29A1 gene, a molecular target for cannabidiol. We emphasize that the novel mode of action of cannabidiol and the previous failures with nontargeted interventions in diabetic retinopathy collectively demand a more rational and personalized clinical development strategy for compounds that have shown promise at the preclinical stage. Moreover, it is noteworthy that ophthalmology, as a medical specialty, has fewer examples (e.g., compared to oncology) of personalized medicine and biomarker applications thus far. Understanding the biological action of cannabidiol in preclinical studies is therefore a rational first step to proactively map the pertinent biomarker strategies in clinical proof of concept studies in diabetic retinopathy, and to allow advances at the hitherto neglected intersection of personalized medicine and ophthalmology.

What Is New in Ophthalmic Research

Several new treatment options have become available for choroidal neovascularization (CNV) in age-related macular degeneration. Fluorescein angiography (FA) used to be the main criterion for treatment and retreatments and was the only evidencebased imaging criterion. Over the last years FA became more and more supplemented by quantitative retinal thickness data and today retreatment often relies on those morphologic data alone. This ongoing transition offers the chance of applying the invasive and time-consuming FA more selectively. However, better knowledge is needed of the relationship between the morphologic retinal thickness changes and the fluorescein angiographic appearance in CNV. The authors therefore investigated this correlation in a well-defined group of classic CNV. One main finding is that imaging results are highly correlated in particular for size measurements, but other parameters such as retinal thickness visualize different properties of the disease process.