Table 1.
Antioxidant, antiapoptotic and anti-inflammatory compounds with demonstrated efficacy in retinal disease. The table compiles proven therapeutic interventions for inherited and induced retinal damage models.
| Compounds | Animal Models of Photoreceptor Degeneration, Diabetic Retinopathy or Retinal Ganglion Cell Death | Clinical Use in Ophthalmology |
|---|---|---|
| Antioxidant and anti-inflammatory |
||
| N-acetylcysteine | IRD and retinal damage models: Rd10 mouse [108,109] P23H rats (studying NLRP3 inflammasome) [59] Blue-light damage in mice [110] Light damage in mice (with angiotensin II type 1 receptor blockade) [111] Light damage in zebrafish [112] Cypermethrin-induced damage in rats [113] AMD: Choroidal neovascularization in mice (studying plasma-activated medium) [114] Autoimmune uveitis in mice [115,116] Diabetic mice (Redd1−/−) [117] Diabetic rats [118] Mouse normal tension glaucoma [119] Choroidal neovascularization in rats [120] |
IRD: RP: NCT03063021 (FIGHT-RP1), NCT04864496 (NAC) [121,122] AMD: NCT03919019 (Macuprev) [123] |
|
N-acetylcysteine
amide |
IRD and retinal damage models: Rd10 mice [124] Light injury in mice [125] |
IRD: Usher syndrome: NCT04355689 (SLO RP) |
| Thioredoxin | IRD and retinal damage models: Rd1 mice [126] Nxlnl1−/− mice after light damage [127] DR models: Diabetic mice with light damage [128] Ganglion cell damage models: Perinatal hypoxia-ischemia retina damage in rats |
|
| Saffron | IRD and retinal damage models: Light-induced photoreceptor degeneration in rats [129,130,131] P23H rats [132] NMDA-induced damage in mice [133] |
IRD: Stargardt disease: NCT01278277 (STARSAF02) AMD: NCT00951288 [134] |
| Minocycline | IRD and retinal damage models: Rhodopsin−/− mice [135] (Mertk)−/− Cx3cr1GFP/+ Ccr2RFP/+ mice [136] P23H and RC rats [137] rd10 mice [138] Rds mice [139,140] NMDA-induced damage in mice [141,142] S100B retina degeneration model [143] Branch retinal vein occlusion in rats [144] Lipofuscinosis: Cln3Δex7/8 mouse [145] Focal light damage in mouse [146] Light damage in mice [147,148] Light damage in rats [149] AMD models: Aging: Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO) [150] Subretinal hemorrhage in mouse [151] DR models: Diabetes rats (histone levels) [152] Diabetes rats (STZ) [153,154] Ganglion cell damage models: Ischemia/reperfusion mice [155,156] Ischemia/reperfusion rats [157,158,159] Glaucoma model in rats [160,161] and mice [162] DBA/2J mouse model of glaucoma [163,164] Optic nerve transection in rats [156] and mice [155] Optic nerve crush mice [165] Axotomy in rat [166] |
IRD: RP: NCT04068207; NCT02140164 AMD: NCT02564978 NCT00893724 DR: Diabetic macular edema: NCT01120899 |
| Melatonin | IRD and retinal damage models: P23H rats [167,168] Rd10 mice [169] Rds mice [170] Light damage in mice [171] MNU-induced photoreceptor degeneration in mice [172] Toxoplasma retinochoroiditis in SD rats (melatonin + zinc) [173] AMD models: Laser-induced CNV in mice [174] Non-exudative AMD after cervical ganglionectomy in mice [175] DR models: STZ rats [176,177,178,179,180,181,182,183] STZ-nicotinamide rats [184] High-fat diet + STZ in mice [185] For review [186] Ganglion cell-damage models: Hypoxia-ischemia mice [187] Ischemia-reperfusion guinea pig [188] |
AMD: Effect of melatonin on AMD [189] Macular damage with blue filtering IOL: NCT00444249 DR: NCT04547439 NCT03478306 |
| Curcumin | IRD and retinal damage models: P23H swine model of RP [190] P23H rat [191] MNU-induced photoreceptor apoptosis in SD rats [192] Light-induced retinal degeneration in rats [193] DR models: Diabetic rats [194,195,196,197,198,199,200,201,202,203,204] Rabbit model of proliferative retinopathy [205] Other retinal diseases models: CLN6 (neuronal ceroid lipofuscinosis) mice [206] Ganglion cell damage models: Rat ischemia/reperfusion [207,208] Retinal ischemia/reperfusion in a rat stroke model [209] Chronic methanol intoxication in rats [210] |
AMD: NCT04590196 NCT05062486 (resveratrol + quercetin + curcumin) DR: Chronic diabetic macular edema [211] In DR, NCT04378972 (curcumin + homotaurine + vitamin D3) In diabetic macular edema, NCT03598205 (Curcumin + dexamethasone) |
| Quercetin | IRD and retinal damage models: Rd10 mice (+ naringenin) [212] P23H rats Light damage in mice (quercertin + myricetin) [213] Blue-light damage in Balb-c mice [214] Light damage in rats [215] AMD models: Nrf2−/− mice [216] DR models: Zebrafish model of DR [217] Diabetic rat retina [218,219] Other retinal disease models: Rodent model of retinopathy of prematurity [220] Ganglion cell damage models: Chronic glaucoma rat model [221] Ischemia/reperfusion in rats [222] |
|
|
Lutein (L)
Zeaxanthin (Z) |
IRD and retinal damage models: Light damage retinopathy in quails (L) [223] and rodents (Z&L) [224,225] Rd1 mice (L + Z + lipoic acid + glutathione + Lycium barbarum) [226] Pde6b rd10 mice [224] Light-induced retinopathy (L&Z) [227] DR models: Diabetic rats, zeaxanthin [228] Light-exposed retinas of mice [229] Other retinal disease models: Inflammatory state of retina in obesity-induced high-fat diet [230] Sod2−/− mice (Z) [231] Vldlr−/− mice [232] House finch vision with carotenoids supplementation (Z or astaxanthin) [233] |
AMD: NCT03919019; NCT00121589; NCT00527553; NCT00564902; NCT01269697; NCT01648660; NCT00763659; NCT01646047; NCT04741763; NCT01694680; NCT00879671 (L) Dietary supplement for AMD: NCT04496817; NCT00345176; NCT01404845; NCT00902408 (L); NCT01527435 (Z); NCT02287298 (Z); NCT02113254 (Z) Aging: NCT02147171 DR: NCT04496817; NCT01627977 Multiple compounds: NCT04117022; NCT04071977; NCT03702374 Other diseases: Corioretinopathy: NCT00963131 Albinism: NCT02200263 Juxtafoveal telangiectasia: NCT01354093 Glaucoma: NCT04460365; NCT03959592; NCT01646047 (Multiple compounds) |
| Catechins | IRD and retinal damage models: P23H1 rats [234,235] Light-induced photoreceptor degeneration in mice [236] Light damage in albino rats [237] Oxidative damage by SNP injection in rats [238] Sodium-iodate-induced retinal degeneration in rats [239] Photoreceptor apoptosis by injection of MNU in SD rats [240] NMDA excitotoxicity in rats [241] DR models: Diabetic rats [242] Ganglion cell damage models: Ischemia/reperfusion in rats [243] Glaucoma model in mice [244] Ischemia/reperfusion in albino rabbits [238] |
AMD: NCT03205202 (Cocoa supplement with 80 mg epicatechins) Supplementation with flavonoids (epigallocatechin, quercetin, etc.) [245] |
| Resveratrol | IRD and retinal damage models: Rd10 mice [246] Light-damaged rat retinas [247] Light damage, mouse [248] Zebrafish model of retinal neurodegeneration by NMDA [249,250] AMD and CNV models: Aging zebrafish retinas [249] Aged SAMP8 mice [251] Choroidal neovascularization mouse model [252]; resveratrol + omega 3 [253] DR models: STZ-induced diabetes in mice [254,255,256] Diabetic rats [257,258,259,260,261,262,263,264] Other retinal disease models: Retinal detachment in Brown Norway rats by subretinal injection of sodium hyaluronate [265] Induced myopia in golden Syrian hamsters [266] Vldlr−/− mice, model of macular telangiectasia [267] Rats with oxygen-induced retinopathy of prematurity [268] Oxygen-induced retinopathy model, SD rats [269] Ganglion cell-damage models: Mouse model ischemia/reperfusion [268,270,271,272] Ischemia/reperfusion Sprague-Dawley rats [273,274,275,276] Mouse model ocular of hypertension (ischemia/reperfusion) [277] Rat chronic ocular hypertension model [278] Steroid-induced ocular hypertensive rats [279] Glaucoma model by injecting hyaluronic acid, Wistar albino rats [280]: riluzole + resveratrol Optic nerve crush in mice [281] Optic nerve transection in SD rats [282] Uveitis models: Inflammation model by LPS injection in mice [283] |
NCT02321176 (pharmacokinetics of resveratrol in the eye) AMD: NCT02625376; NCT04756310: supplementation in AMD [284] Observer-blinded trial in wet AMD patients (lutein, zeaxanthin, resveratrol, hydroxytyrosol and DHA+ the AREDS EU recommended doses) [284] NCT05062486: resveratrol + quercetin + curcumin for AMD Case report (resveratrol + lutein + Vac. myrtilus) in AMD patient [285] Octogenarians + resveratrol supplement [286] DR: Observational study with diabetic patients. Supplementation with multinutrient complex (resveratrol + vitamins, L, Z, etc.) [287] NCT04117022: diabetic retinopathy (rich formula) NCT03866005: Adjunctive Carotenoids Plus Antioxidants in Anti-VEGF Treated Diabetic Macular Edema (PROACTIVEDME)Other:Effect on choroidal thickness, in young and healthy:NCT02321189 |
| Dietary antioxidants | IRD and retinal damage models: Tested individual effects of vitamins in dystrophic RCS rats [288] LED light damage rats (β-Cryptoxanthin) [289] Light damage in SD rats (AREDS ± antioxidants) [290] Light damage in rats (suppl antioxidants and omega 3) [291] Light damage in rats (Beta carotene) [292] Light rabbit (blueberry polyphenols) [293] AMD and CNV models: CNV mice (Resvega: omega 3 + resveratrol) [252] 𝛽Amyloid mice (grape seed extracts) [294] β5−/− mice [295] Other retinal disease models: Smith–Lemli–Opitz syndrome (defective cholesterol synthesis) [296] ApoE−/− mice. Suppl L vs. multivitamin [297] DR models: Diabetes, rats (ascorbic acid, vitamin E, beta-carotene, zinc, and copper) [298] Diabetes rats (carrot powder) [299] Diabetes and experimental galactosemia in rats (antioxidants, ascorbic acid, alpha-tocopherol) [300] Diabetes and experimental galactosemia in rats VI (ascorbic acid + trolox + alpha-tocopherol + NAC+ beta-carotene + selenium) [301] Ganglion cell damage models: Ischemia/reperfusion mice with ubiquinol [302] Pressure trauma in mice [303] |
AMD: AMD prevention [304] NCT03326401; NCT04756310; NCT02264938; NCT00121589; NCT00800995 NCT00000145 (AREDS); NCT00345176 (AREDS2) DR: NCT04496817 Other diseases: Retinopathy of prematurity NCT03866005 Hyperoxia-induced retinal reduced blow flow: NCT00712907 Oxygen-induced retinal vasoconstriction: NCT02221089ithout DR |
| Fructus lycii | IRD and retinal damage models: Rd10 mouse [305] Methyl-N-nitrosurea photoreceptor degeneration mouse model Rd1 mice (L + Z+ lipoic acid + glutathione + Lycium barbarum) [226] Light damage in rats [306] Light damage in mice [307] Intravitreal paraquat in rats [308] DR models: Diabetic rats [309] Other retinal diseases models: Alzheimer’s Disease Model Mouse Retina [310] Ganglion cell damage models: Ischemia/reperfusion in rats [311] Acute hypertension in mice [312,313] Ocular hypertension in rats [314,315,316] |
IRD: RP: NCT02244996 (Lycium barbarum) [317] AMD: Goji berry intakes and macular pigment in healthy adults (randomized pilot study) [318] |
| Alpha-lipoic acid | IRD and retinal damage models: Rd1 mice (L + Z + lipoic acid + glutathione + Lycium barbarum) [226] Rd1 mouse (mixture) [319]. Rd10 model (α-tocopherol, ascorbid acid, α-lipoic acid) [320] Q334 model (α-tocopherol, ascorbid acid, α-lipoic acid) [320] Rd1 model (LA and/or progesterone) [321] |
AMD: NCT02613572 DR: NCT01880372 |
| (Z)-7,4′-Dimethoxy-6-hydroxy-aurone-4-O- β -glucopyranoside (DHAG) | IRD and retinal damage models: Rd10 mouse [322] |
|
| Multi-target iron chelators | IRD and retinal damage models: Mouse model of RP [323] Rd 10 mice [324,325] NMDA damage in rats [326] |
|
| Creatine | IRD and retinal damage models: Rd1 mice [327] |
Gyrate atrophy with hyperornithinaemia (4 patients) [328] Gyrate atrophy (7 patients) [329] |
| Sulforaphane | IRD and retinal damage models: Phd6b rd10 mice [330] Light damage mice (sulforaphane induces TRX) [331] Light damage mice [332] Tubby mouse [333] DR models: Diabetic STZ rats [334] Ganglion cell damage models: Rat model ischemia reperfusion [335] Ischemia in mice [336] |
|
| NOS inhibitors | IRD and retinal damage models: Rd1 mice [337] S334ter-3 rat [338] Light damage in rats [339] Ganglion cell damage models: Rat model of chronic glaucoma [340,341] Rat axotomy [342] |
|
|
Sigma1R ligand (+)-
Pentazocine (PTZ) |
IRD and retinal damage models: Rd10 mice [343,344,345,346,347] NMDA damage in mice [348] DR models: Diabetic mice Ins2(Akita/+) [349,350] Ganglion cell damage models: Optic nerve crush in mice [351] |
|
|
Norbixin
(bixin extracted from Bixa Orellana) |
IRD and retinal damage models: Blue-light model of photodamage in rats [352] Abca4−/− Rdh8−/− mice [353] |
|
| (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one | IRD and retinal damage models: Pde6b rd10 mice [354] |
|
| Glycyrrhizic acid/Glycyrrhizin | IRD and retinal damage models: IGFB-3 KO mouse [355] Blue-light-induced damage in mouse [356] DR models: Diabetic rats [357,358] Ganglion cell damage models: Acute model of glaucoma in mice [359] Ischemia-reperfusion in mice [360] |
|
| Antiapoptotic agents | ||
| Tudca | IRD and retinal damage models: P23H AD rat model [361] MNU-induced photoreceptor degeneration mouse model [362] Leber Congenital Amaurosis mouse [363] Rd1 mice [364] Rd10 mice [365] Rd1, Rd10, Rd16 (Bardet–Biedl Syndrome type 1) [366] Light-induced damage in mice [367] RPGR conditional knockout (cko) mouse [368] NMDA-induced damage in mice [369] AMD and CNV models: CNV laser-induced rat [370] DR models: Mouse model of type 1 diabetes [371] Ex vivo model of RD in rats [372] Other retinal diseases models: Retinal detachment rat model [373] Ganglion cell damage models: Rat optic nerve crush [374] |
Others: Rhegmatogenous RD: NCT02841306 URSO |
| Rasagiline | IRD and retinal damage models: Rd10 mice (RP) [375] Prph2/rds mouse [376] Ganglion cell damage models: Glaucoma model in rats [377] Mouse, ischemia/reperfusion [378] (rasagiline + idebenone) |
Others: Retinal detachment: NCT02068625 (Macula off- retinal detachment) [379] |
|
Norgestrel/
Progesterone |
IRD and retinal damage models: Pde6b Rd10 mouse [380,381,382] Rd1 mice (L + Z + lipoic acid + glutathione + Lycium barbarum) Rd1 mouse [383] Rd10 mice [384] Acute light-induced degeneration model in mice [382,385] Ganglion cell damage models: Rat models of ocular ischemia [386] Review: [387] |
|
| Proinsulin | IRD and retinal damage models: Rd10 mice [388] P23H RP rats [389] |
Others: Glaucoma NCT05206877, NCT04118920 |
| Nutraceuticals and other compounds | ||
|
Anthocyanin
Cyanidin-3-glucoside (C3G) Bilberry extract |
IRD and retinal damage models: Light-induced photoreceptor degeneration in rats (+L) [390] Light damage in rabbits [391] MNU-induced damage in rats [392] Other retinal disease models: Oxygen-induced retinopathy in mice [393] IRD and retinal damage models: Photo-stressed murine model [394] Light damage in rabbits [395] AMD models: OXYS rats [396] DR models: STZ rats [397] Other retinal disease models: Oxygen-induced retinopathy in mice [398] Ganglion cell damage models: Optic nerve crush in mice [399] Uveitis models: Endotoxin-induced uveitis in mice [400] |
Metabolism and Clearance of Cyanidin 3 Glucoside: NCT01106729 NCT01942746: Blueberry Effects on Dark Vision and Glare Recovery [401] |
| 4-Phenylbutyric acid | IRD and retinal damage models: Photo-stressed murine model [402] P23H mice [403] Leber congenital amaurosis mice [404] Other retinal disease models: Hypoxia mice [405] Ganglion cell damage models: Ischemic optic neuropathy in mice [406] Ischemic rats [407] |
IRD: Achromatopsia NCT04041232 |
| Celastrol | IRD and retinal damage models: Light-induced retinal degeneration mice [408] Ganglion cell damage models: Ocular hypertension in mice [409] Optic nerve crush [410] |
|
| Salvia miltiorrhiza Bunge | IRD and retinal damage models: Light damage in mice [411] Rd10 mice (+ Fructus lycii) DR models: DR rats (FXST Chinese medicine + various compounds) |
|
| Vitamin A and/or E | Vitamin A IRD and retinal damage models: Lrat−/−, Rpe65−/−, and Gnat1−/− mouse models, supplemented with Vit A derivatives [412] T17M mouse [413] DR models: DR rat [414,415] Other retinal pathology models: Obesity-associated retinal degeneration in WNIN/Ob rats [416] Vitamin E IRD and retinal damage models: Radiation induced retinal damage in a rat model [417] Light-induced damage in guinea pig [418] Light damage in albino mice [419] DR models: Diabetic rats (taurine, Vit E + selenium) [420] Other retinal pathology models: Porcine hypercholesterolemia [421] |
Vitamin A IRD: RP: NCT00000116 (vitamin A + fish oils) [422]; NCT00346333 (L + vit A); NCT04499820 (flavonoids, L, Z) Choroidemia: NCT05045703 Stargardt disease (ALK-001): NCT02230228; NCT04239625; NCT02402660 LCA, RP Drug: QLT091001, NCT01014052 Night blindness in Sorsby’s fundus dystrophy [423] AMD: AMD Review [424] AMD, reticular pseudodrusen: NCT03478878 AMD: NCT03478865 Geographic atrophy: NCT03845582 AMD (Phase I): NCT02230228 Others: Retinopathy of Prematurity: NCT00417404; NCT03154723; NCT03779776 (Vit AD); NCT02102711 DR: NCT04000789 (Vit A, Vit E); NCT04000789 Vitamin E IRD: RP: NCT00000114 (Vit A + Vit E) [425] AMD: NCT00784225; NCT00000161; NCT00893724; NCT00893724; NCT00000145 (various antioxidants) DR: NPDR (various compounds) [426] Others: Glaucoma: NCT01544192 Retinopathy of Prematurity: NCT03274596 |
Abbreviations: IRD, inherited retinal dystrophies; AMD, age-related macular degeneration; DR, diabetic retinopathy; CNV, choroidal neovascularization; RP, retinitis pigmentosa; LCA, Leber Congenital Amaurosis; STZ, streptozotocin, MNU, N-methyl-N-nitrosourea; NMDA, N-methyl-D-aspartate; L, Lutein; Z, Zeaxanthin; NAC, N-acetylcysteine; DHA, docosahexaenoic acid; NOS, nitric oxide synthase.