See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/311895248 The arguments for and against cannabinoids application in glaucomatous retinopathy Article in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · February 2017 DOI: 10.1016/j.biopha.2016.11.106 CITATIONS READS 0 86 4 authors: Yunes Panahi Azadeh Manayi Baqiyatallah University of Medical Sciences Tehran University of Medical Sciences 191 PUBLICATIONS 1,332 CITATIONS 67 PUBLICATIONS 169 CITATIONS SEE PROFILE SEE PROFILE Marjan Nikan Mahdi Vazirian Tehran University of Medical Sciences Tehran University of Medical Sciences 10 PUBLICATIONS 17 CITATIONS 23 PUBLICATIONS 52 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Clinical trial of some medicinal plants, used in traditional medicine View project Analysis of natural products View project All content following this page was uploaded by Mahdi Vazirian on 29 December 2016. 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Biomedicine & Pharmacotherapy 86 (2017) 620–627 Available online at ScienceDirect www.sciencedirect.com Review The arguments for and against cannabinoids application in glaucomatous retinopathy a b b c, Yunes Panahi , Azadeh Manayi , Marjan Nikan , Mahdi Vazirian * a Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran b Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran c Pharmacognosy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran A R T I C L E I N F O A B S T R A C T Article history: Received 29 October 2016 Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive Received in revised form 21 November 2016 retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable Accepted 27 November 2016 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 Keywords: effect of these agents has been recently described through modulation of endocannabinoid system in the Cannabis sativa eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of Endocannabinoid system exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and Glaucoma neuroprotection property of cannabinoids will be discussed according to current scientific literature. In Intraocular pressure addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of Marijuana Neuroprotection application of cannabinoids in glaucoma will be reviewed. © 2016 Elsevier Masson SAS. All rights reserved. Contents 1. Introduction . 1 2. Natural source of cannabinoids . 3 3. Biosynthesis of cannabinoids . 3 4. Chemistry and bioavailability of some natural cannabinoids . 3 5. Endocannabinoid system in the eye . 3 6. Effects of cannabinoids in lowering of IOP . 3 7. Effects of cannabinoids in neuroprotection . 4 8. Adverse effects of marijuana . 5 9. Discussion . 5 Conflict of interest . 6 References . 6 1. Introduction humor formation and draining out, is the only known modifiable risk factor for prevention of glaucoma progress. Although, the Glaucoma, a neurodegenerative eye disease, known as a major elderly are at higher risk for the disease, glaucoma can develop in factor for irreversible blindness. It is predicted that more than 80 young adults, children, and infants [2,3]. Damage of optic nerve million people by 2020 will be affected by glaucoma leading to at most commonly occurs due to high IOP and progressive least 6–8 million bilaterally blind worldwide [1]. Increased degeneration of retinal ganglion cells (RGCs) leading to irreversible intraocular pressure (IOP) >22 mmHg, due to imbalance of aqueous vision loss [4]. Blood flow alteration as a result of IOP, produces hypoxia and ischemia in the retina and optic nerve [5]. Standard treatments are restricted to reduction of IOP using medications or surgery. While, these types of treatments are not effective in some * Corresponding author. patients and a subset of glaucoma is not associated with high IOP E-mail address: [email protected] (M. Vazirian). http://dx.doi.org/10.1016/j.biopha.2016.11.106 0753-3322/© 2016 Elsevier Masson SAS. All rights reserved. Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627 621 [6]. Protection of retinal ganglion cells from damage and death enzymes of their synthesis and metabolism and cannabinoid directly can be considered as a novel approach to combat glaucoma receptors in the retina [15]. The physiological and pharmacological [7]. activities of endocannabinoids along with natural and synthetic Resin glands located on secreting trichomes of female-plant cannabinoids are mediated mostly by two receptors, cannabinoid flowers of Cannabis sativa (Cannabaceae family) contain consider- receptor 1 (CB1) and cannabinoid receptor 2 (CB2) [13]. Receptors able amount of cannabinoids. Smaller quantity of these chemically of CB1 are predominantly expressed in the central nervous system active compounds was found in the leaves of the cannabis plant (CNS), while receptors of CB2 are mainly located in peripheral (marijuana) [8]. Several cannabinoids have been isolated of the tissues and immune system and also found in the CNS [16–18]. plant, of which D9-tetrahydrocannabinol (D9-THC), cannabichro- Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachido- mene (CBC), cannabigerol (CBG), cannabinol (CBN) and cannabi- noylglycerol (2-AG) (Fig. 1) are the two most studied endogenous diol (CBD) are the most relevant in the amount of cannabinoids. cannabinoids. Endocannabinoids also activate other targets, Synthetic modulators of endogenous cannabinoid system has been including non-CB1, non-CB2 G-protein-coupled receptors and also investigated for their therapeutic potentials in addition to various ion channels [19]. Therapeutic effects of cannabinoids in phytocannabinoids (Fig. 1) [9]. These compounds possess thera- CNS pathologies like Parkinson’s disease, Alzheimer’s disease, peutic effects on cancer, pain, emesis, inflammation, obesity, and Huntington disease, head trauma, and multiple sclerosis (MS) have neurodegenerative diseases along with other psychotropic prop- been reported in the previous studies [20–24]. In this review, the erties [10–13]. knowledge of therapeutic potential of cannabinoids will be The beneficial function of cannabinoids in ocular physiology particularly discussed in glaucoma. Relevant information regard- and disease dates back to 1971 when it was reported that smoking ing chemistry and bioavailability of cannabinoids, the ocular marijuana lower the IOP [14]. Role of cannabinoids in retinal endocannabinoid system, and ocular hypotensive as well as circuitry and vision is supported by the presence of the functional neuroprotective properties of cannabinoids will be provided in endocannabinoid system including endogenous cannabinoids, the treatment of glaucoma. OH OH O OH OH O O 2-arachidonyl glycerol (2-AG) 2-arachidonyl glyceryl ether OH H O OH N OH N O H anandamide (AEA) N-arachidonyl dopamine (NADA) Endocannabinoids OH H OH OH H H H O O HO delta9-tetrahydrocannabinol cannabinol cannabidiol Natural cannabinoids O HO O OH H H O H N O O H N O WIN55212-2 nabilone dronabinol Synthetic cannabinoids Fig. 1. Chemical structures of some cannabinoids. 622 Y. Panahi et al. / Biomedicine & Pharmacotherapy 86 (2017) 620–627 2. Natural source of cannabinoids formula of C21H26O2, molecular mass 310.4319 g/mol, was isolated from the plant cannabis. Average bioavailability of inhaled CBN is Cannabis has three specious including C. sativa, Cannabis indica, 38% (range 8–65%) [9,33,45]. and Cannabis ruderalis. About 113 cannabinoids with various effects were isolated from C. sativa which is an annual herbaceous 5. Endocannabinoid system in the eye plant [25]. There are some studies indicate that C. indica contains higher amount of D9-THC than CBD, while C. sativa have more In addition to the human retina, presence of CB1 and CB2 has amount of CBD [26]. Wild specious of cannabis, C. ruderalis, lack been shown in several specious. Generally, CB1 is found in cones, meaningful quantity of psychoactive cannabinoids [27]. horizontal cells, amacrine, some bipolar cells, RGCs, and ganglion cell axons [13,46–49]. In human, receptors of CB1 are expressed in 3. Biosynthesis of cannabinoids outer segments of photoreceptor cells, outer plexiform layer, inner plexiform layer, two synaptic layers of the retina, inner nuclear Cannabinoids are primarily synthesized in glandular trichomes layer, ganglion cell layer, and retinal pigment epithelium cells. CB2 of flowers and, to a lesser extent, leaves of the female plant from receptors are found in human retinal pigment epithelium cells fatty acid and isoprenoid precursors [28]. A type III polyketide [47,50,51]. Immunocytochemical methods revealed that transient synthase is the first enzyme in the cannabinoid synthesis pathway receptor potential vanilloid type 1 (TRPV1), a ligand-gated, which catalyzes hexanoyl-CoA condensation with