Cannabinoids as New Drug Candidates for the Treatment of Glaucoma

Erin Jordan; Gia-Nam Nguyen; Alexander Piechot; Oliver Kayser

doi:10.1055/a-1665-3100

Planta Medica, Table of Contents

Planta Med 2022; 88(14): 1267-1274
DOI: 10.1055/a-1665-3100

Biological and Pharmacological Activity

Reviews

Cannabinoids as New Drug Candidates for the Treatment of Glaucoma

Erin Jordan‡

¹Technical Biochemistry, TU Dortmund University, Dortmund, Germany

,

Gia-Nam Nguyen ‡

¹Technical Biochemistry, TU Dortmund University, Dortmund, Germany

²MINDbioscience GmbH, Dortmund, Germany

,

Alexander Piechot

²MINDbioscience GmbH, Dortmund, Germany

,

Oliver Kayser

¹Technical Biochemistry, TU Dortmund University, Dortmund, Germany

› Author Affiliations

Abstract

Glaucoma is a blinding eye disease that affects about 70 million patients globally today. The cannabinoid receptors and the endocannabinoid system have found attention for new drug concepts. This review will analyze the potential of cannabinoids, primarily tetrahydrocannabinol, THCVS, and cannabinol, as drug candidates and the role of CB1/CB2 receptors with regard to the pathophysiology of glaucoma. The mode of action of cannabinoids as innovative drug candidates and recent formulations for topical delivery will be discussed. Cannabinoid receptors with associated TRPV channels will be evaluated for their potential as drug targets. Especially the role of the endocannabinoid system (fatty acid amide hydrolase, monoacylglycerol lipase) impacting the prostaglandin network (cyclooxygenase, PGE, PGF) and neuroprotection by inhibition of nitric oxide radical formation is in the focus of this review. Delivery systems, including recent clinical trials, will be analyzed to evaluate the potential for innovative future ophthalmological drugs.

Key words

tetrahydrocannabinol - cannabidiol - cannabinol - intraocular pressure - glaucoma - endocannabinoid system - COX-2 - MAGL

Full Text

References

References
1 Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol 2012; 96: 614-618
2 Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology 2014; 121: 2081-2090
3 Barkana Y, Dorairaj S. Re: Tham et al.: Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis (Ophthalmology 2014; 121: 2081–90). Ophthalmology 2015; 122: e40-e41
4 Chen MJ. Normal tension glaucoma in Asia: Epidemiology, pathogenesis, diagnosis, and management. Taiwan J Ophthalmol 2020; 10: 250-254
5 Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet 2017; 390: 2183-2193
6 Medeiros FA, Weinreb RN. Medical backgrounders: Glaucoma. Drugs Today (Barc) 2002; 38: 563-570
7 Lee DA. Ocular hypotensive medications for the treatment of glaucoma. Ophthalmol Clin North Am 2005; 18: 529-538
8 Romano MR, Lograno MD. Evidence for the involvement of cannabinoid CB1 receptors in the bimatoprost-induced contractions on the human isolated ciliary muscle. Invest Ophthalmol Vis Sci 2007; 48: 3677-3682
9 Perry CM, McGavin JK, Culy CR, Ibbotson T. Latanoprost: An update of its use in glaucoma and ocular hypertension. Drugs Aging 2003; 20: 597-630
10 Panarese V, Moshirfar M. Pilocarpine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021
11 Lusthaus JA, Goldberg I. Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation. Expert Opin Drug Saf 2017; 16: 1071-1078
12 Inoue T, Tanihara H. Ripasudil hydrochloride hydrate: Targeting Rho kinase in the treatment of glaucoma. Expert Opin Pharmacother 2017; 18: 1669-1673
13 Green K. Marijuana smoking vs. cannabinoids for glaucoma therapy. Arch Ophthal 1998; 116: 1433-1437
14 Novack GD. Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol 2016; 27: 146-150
15 Hepler RS, Frank IR. Marihuana smoking and intraocular pressure. JAMA 1971; 217: 1392
16 Perez-Reyes M, Lipton MA, Timmons MC, Wall ME, Brine DR, Davis KH. Pharmacology of orally administered 9 -tetrahydrocannabinol. Clin Pharmacol Ther 1973; 14: 48-55
17 Merritt JC, Perry DD, Russell DN, Jones BF. Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma. J Clin Pharmacol 1981; 21: 467S-471S
18 Devane WA, Dysarz 3rd FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605-613
19 Straiker AJ, Maguire G, Mackie K, Lindsey J. Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol Vis Sci 1999; 40: 2442-2448
20 Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: A unified critical inventory. Nat Prod Rep 2016; 33: 1357-1392
21 Nguyen G-N, Kayser O. Biosynthesis and Chemical Modifications of Minor Cannabinoids. In: eLS Chichester: John Wiley & Sons, Ltd; 2020
22 Garrett ER, Hunt CA. Physicochemical properties, solubility, and protein binding of delta9-tetrahydrocannabinol. J Pharm Sci 1974; 63: 1056-1064
23 Miller S, Daily L, Leishman E, Bradshaw H, Straiker A. Δ9-tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Invest Ophthalmol Vis Sci 2018; 59: 5904-5911
24 Brown AJ. Novel cannabinoid receptors. Br J Pharmacol 2009; 152: 567-575
25 Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 129-180
26 Thakur GA, Nikas SP, Makriyannis A. CB1 cannabinoid receptor ligands. Mini Rev Med Chem 2005; 5: 631-640
27 López EM, Tagliaferro P, Onaivi ES, López-Costa JJ. Distribution of CB2 cannabinoid receptor in adult rat retina. Synapse 2011; 65: 388-392
28 Bouskila J, Javadi P, Casanova C, Ptito M, Bouchard JF. Müller cells express the cannabinoid CB2 receptor in the vervet monkey retina. J Comp Neurol 2013; 521: 2399-2415
29 de Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, Di Marzo V. Cannabinoid actions at TRPV channels: Effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 2012; 204: 255-266
30 Assimakopoulou M, Pagoulatos D, Nterma P, Pharmakakis N. Immunolocalization of cannabinoid receptor type 1 and CB2 cannabinoid receptors, and transient receptor potential vanilloid channels in pterygium. Mol Med Rep 2017; 16: 5285-5293
31 Cairns EA, Baldridge WH, Kelly MEM. The endocannabinoid system as a therapeutic target in glaucoma. Neural Plast 2016; 2016: 9364091
32 Wang MTM, Danesh-Meyer HV. Cannabinoids and the eye. Surv Ophthalmol 2021; 66: 327-345
33 Gregus AM, Buczynski MW. Druggable targets in endocannabinoid signaling. Adv Exp Med Biol 2020; 1274: 177-201
34 Alhouayek M, Muccioli GG. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 2014; 35: 284-292
35 Yu M, Ives D, Ramesha CS. Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 1997; 272: 21181-21186
36 Berglund BA, Boring DL, Howlett AC. Investigation of structural analogs of prostaglandin amides for binding to and activation of CB1 and CB2 cannabinoid receptors in rat brain and human tonsils. Adv Exp Med Biol 2000; 469: 527-533
37 Caldwell MD, Hu SSJ, Viswanathan S, Bradshaw H, Kelly ME, Straiker A. A GPR18-based signalling system regulates IOP in murine eye. Br J Pharmacol 2013; 169: 834-843
38 Miller S, Hu SSJ, Leishman E, Morgan D, Wager-Miller J, Mackie K, Bradshaw HB, Straiker A. A GPR119 signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner. Invest Ophthalmol Vis Sci 2017; 58: 2930-2938
39 Zantut PRA, Veras MM, Yariwake VY, Takahashi WY, Saldiva PH, Young LH, Damico FM, Fajersztajn L. Effects of cannabis and its components on the retina: A systematic review. Cutan Ocul Toxicol 2020; 39: 1-9
40 Leishman E, Manchanda M, Thelen R, Miller S, Mackie K, Bradshaw HB. Cannabidiolʼs upregulation of N-acyl ethanolamines in the central nervous system requires N-acyl phosphatidyl ethanolamine-specific phospholipase D. Cannabis Cannabinoid Res 2018; 3: 228-241
41 El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI. Neuroprotective effect of(−)Δ9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: Involvement of peroxynitrite. Am J Pathol 2003; 163: 1997-2008
42 Miller S, Daily L, Dharla V, Gertsch J, Malamas MS, Ojima I, Kaczocha M, Ogasawara D, Straiker A. Endocannabinoid metabolism and transport as targets to regulate intraocular pressure. Exp Eye Res 2020; 201: 108266
43 Fezza F, Bari M, Florio R, Talamonti E, Feole M, Maccarrone M. Endocannabinoids, related compounds and their metabolic routes. Molecules 2014; 19: 17078-17106
44 Maia J, Midão L, Cunha SC, Almada M, Fonseca BM, Braga J, Gonçalves D, Teixeira N, Correia-da-Silva G. Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta. Arch Toxicol 2019; 93: 649-658
45 Miller S, Leishman E, Hu SS, Elghouche A, Daily L, Murataeva N, Bradshaw H, Straiker A. Harnessing the endocannabinoid 2-arachidonoylglycerol to lower intraocular pressure in a murine model. Invest Ophthalmol Vis Sci 2016; 57: 3287-3296
46 Reina-Torres E, de Ieso ML, Pasquale LR, Madekurozwa M, van Batenburg-Sherwood J, Overby DR, Stamer WD. The vital role for nitric oxide in intraocular pressure homeostasis. Prog Retin Eye Res 2021; 83: 100922
47 Green K, Roth M. Ocular effects of topical administration of delta9-tetrahydrocannabinol in man. Arch Ophthalmol 1982; 100: 265-267
48 Passani A, Posarelli C, Sframeli AT, Perciballi L, Pellegrini M, Guidi G, Figus M. Cannabinoids in glaucoma patients: The never-ending story. J Clin Med 2020; 9: 3978
49 Newell FW, Stark P, Jay WM, Schanzlin DJ. Nabilone: A pressure-reducing synthetic benzopyran in open-angle glaucoma. Ophthalmology 1979; 86: 156-160
50 Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of sublingual application of cannabinoids on intraocular pressure: A pilot study. J Glaucoma 2006; 15: 349-353
51 Kompella UB, Hartman RR, Patil MA. Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma. Prog Retin Eye Res 2021; 82: 100901
52 Gote V, Sikder S, Sicotte J, Pal D. Ocular drug delivery: Present innovations and future challenges. J Pharmacol Exp Ther 2019; 370: 602-624
53 Taskar PS, Patil A, Lakhani P, Ashour E, Gul W, ElSohly MA, Murphy B, Majumdar S. Δ9-tetrahydrocannabinol derivative-loaded nanoformulation lowers intraocular pressure in normotensive rabbits. Transl Vis Sci Technol 2019; 8: 15
54 Adelli GR, Bhagav P, Taskar P, Hingorani T, Pettaway S, Gul W, ElSohly MA, Repka MA, Majumdar S. Development of a Δ 9-tetrahydrocannabinol amino acid-dicarboxylate prodrug with improved ocular bioavailability. Invest Ophthalmol Vis Sci 2017; 58: 2167-2179
55 Elsohly MA, Gul W, Repka MA, Majumdar S. Compositions containing delta-9-THC-amino acid esters and process of preparation. US Patent US8809261B2, 2014
56 Hossain S, Kabiri M, Yadav V. Ocular drug delivery formulation. WIPO Patent 2018/205022 A1, 2018
57 Kabiri M, Kamal SH, Pawar SV, Roy PR, Derakhshandeh M, Kumar U, Hatzikiriakos SG, Hossain S, Yadav VG. A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery. Drug Deliv Transl Res 2018; 8: 484-495
58 Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003; 302: 84-88
59 Keister JC, Cooper ER, Missel PJ, Lang JC, Hager DF. Limits on optimizing ocular drug delivery. J Pharm Sci 1991; 80: 50-53
60 Ryskamp D, Redmon S, Jo AO, Križaj D. TRPV1 and endocannabinoids: Emerging molecular signals that modulate mammalian vision. Cells 2014; 3: 914-938
61 Patel GC, Millar JC, Clark AF. Glucocorticoid receptor transactivation is required for glucocorticoid-induced ocular hypertension and glaucoma. Invest Ophthalmol Vis Sci 2019; 60: 1967-1978
62 Papadogkonaki S, Theodorakis Κ, Thermos K. Endogenous and synthetic cannabinoids induce the downregulation of cannabinoid CB1 receptor in retina. Exp Eye Res 2019; 185: 107694
63 Miller S, Kulkarni S, Ciesielski A, Nikas SP, Mackie K, Makriyannis A, Straiker A. Controlled-deactivation CB1 receptor ligands as a novel strategy to lower intraocular pressure. Pharmaceuticals 2018; 11: 50
64 Gil D, Spalding T, Kharlamb A, Skjaerbaek N, Uldam A, Trotter C, Li D, WoldeMussie E, Wheeler L, Brann M. Exploring the potential for subtype-selective muscarinic agonists in glaucoma. Life Sci 2001; 68: 22-23
65 Miller S, Daily L, Ploss M, Greig I, Ross R, Rayana NP, Dai J, Sugali CK, Mao W, Straiker A. Evidence that cannabinoid CB1 receptors regulate intraocular pressure via two opposing mechanisms. Exp Eye Res 2020; 200: 108241
66 Tiedeman JS, Shields MB, Weber PA, Crow JW, Cocchetto DM, Harris WA, Howes JF. Effect of synthetic cannabinoids on elevated intraocular pressure. Ophthalmology 1981; 88: 270-277