Endocannabinoids in the retina: From marijuana to neuroprotection

Abstract

The active component of the marijuana plant Cannabis sativa, Δ 9 -tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the "cannabinergic" field to the retinal community. All of the fundamental work on cannabinoids has been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptation, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases.

The Endocannabinoid System in the Vervet Monkey Retina

“…The presence of CB1 receptors in the retina of many species has been reported [47]. The modulatory effects of cannabinoids, acting on CB1 receptors, at all stages of retinal processing have also been described (For review, see [48]). Furthermore, the cannabinoid receptors (Figure 2) and related enzymes (Figure 3) are expressed in the mouse, tree shrew, vervet monkey, and macaque monkey retina [49].…”

“…These receptors are differently expressed in the retina of these mammals. These results are compiled from several published articles [43,[47][48][49][50][51][52][53][54]. OS, photoreceptor outer segments; IS, photoreceptor inner segments; ONL, outer nuclear layer; ONL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer.…”

“…Further research is also necessary to define the exact signaling pathways used by cannabinoid receptors to regulate retinal cell activity. There is evidence that CB1R regulates photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cell activity through a cAMP-mediated pathway (for review, see [48]), but little is known on how cannabinoids regulate global retinal activity. There have been major inconsistencies between different studies with regard to the expression and function of the ECS in the retina and the brain.…”

New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system

“…Although, several studies have shown that topical administration of cannabinoids reduces IOP (Pate et al, 1995;Laine et al, 2001;Chien et al, 2003) by modulating both production and drainage of aqueous humor (Chien et al, 2003;Njie et al, 2006) a number of studies reported that cannabinoids exert neuroprotective effects in the eye against glutamate-induced excitotoxicity (Jarvinen et al, 2002;Crandall et al, 2007;Nucci et al, 2007bNucci et al, , 2008Duncan et al, 2011), with potential implications for the treatment of glaucoma. (Tomida et al, 2004;Yazulla, 2008). Interestingly, some studies suggested that inhibition of glutamate release represents a key mechanism involved in neuroprotection mediated by the cannabinoid system (Braida et al, 2000;Sinor et al, 2000;Marsicano et al, 2003;Gobira et al, 2015;Lin et al, 2015).…”

Aplicaciones de los cannabinoides en glaucoma

“…Desde el control de la presión intraocular hasta el correcto trofismo de las células ganglionares de la retina, el sistema endocannabinoide endógeno juega un papel importante en la fisiología ocular [75][76][77][78] . El mejor conocimiento de los receptores y las vías a través de las cuales los cannabinoides pueden ejercer sus múltiples efectos oftalmológicos nos llevan a plantear estos fármacos como herramientas terapéuticas para el tratamiento médico del glaucoma.…”