Skip to main content

Advertisement

SpringerLink
Log in

Potential neuroprotective biomolecules in ophthalmology

  • Review
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Purposes

Retinal neurodegenerative diseases are responsible for a huge number of ocular problems worldwide. It seems that the progression of these diseases can be managed by the application of neuroprotective molecules particularly in the early stages. This article focuses on the most common neuroprotective bioagents under investigation in ophthalmology.

Methods

We searched the web of science, PubMed and Scopus databases with these keywords: "glaucoma," "diabetic retinopathy," "age-related macular degeneration," "optic neuropathy and retinal degeneration" and/or "neuroprotection."

Results

The most commonly utilized neuroprotective drugs for ophthalmology diseases were introduced in this study. It seems that these agents can be divided into three categories according to their mechanism of action: (A) neurotrophins, (B) decreasing effect on intraocular pressure and (C) inhibition of retinal neuron apoptosis.

Conclusion

A broad range of drugs has been illustrated in the literature for treatment of neuro-ophthalmic diseases. A good classification of the most applied drugs in this field can help specialists to prescribe the best matched drug considering the stage and progression of disease. However, controlled clinical trials are needed for better evaluation of the effects of these products.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Data availability

Data sharing is not applicable to this article.

Abbreviations

AMD:

Age-related macular degeneration

BDNF:

Brain-derived neuroprotective factor

CNTF:

Ciliary neurotrophic factor

CoQ10:

Coenzyme Q10

DR:

Diabetic retinopathy

IOP:

Intraocular pressure

MS:

Multiple sclerosis

RGC:

Retinal ganglion cells

References

  1. World Health Organization (2007) Global initiative for the elimination of avoidable blindness: action plan 2006–2011. World Health Organization, Geneva

    Google Scholar 

  2. Kocur I, Resnikoff S (2002) Visual impairment and blindness in Europe and their prevention. Br J Ophthalmol 86(7):716–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pardue MT, Allen RS (2018) Neuroprotective strategies for retinal disease. Prog Retinal Eye Res 65:50–76

    Article  CAS  Google Scholar 

  4. Wubben TJ, Zacks DN, Besirli CG (2019) Retinal neuroprotection: current strategies and future directions. Curr Opin Ophthalmol 30(3):199–205

    Article  PubMed  Google Scholar 

  5. Shpak AA, Guekht AB, Druzhkova TA, Kozlova KI, Gulyaeva NV (2018) Brain-derived neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract. Curr Eye Res 43(2):224–231

    Article  CAS  PubMed  Google Scholar 

  6. Jiao S, Shen L, Zhu C, Bu X, Liu Y, Liu C et al (2016) Brain-derived neurotrophic factor protects against taurelated neurodegeneration of Alzheimer’s disease. Transl Psychiatry 6(10):e907-e

    Article  CAS  Google Scholar 

  7. Weber AJ, Viswanáthan S, Ramanathan C, Harman CD (2010) Combined application of BDNF to the eye and brain enhances ganglion cell survival and function in the cat after optic nerve injury. Invest Ophthalmol Vis Sci 51(1):327–334

    Article  PubMed  PubMed Central  Google Scholar 

  8. Uzel AGT, Ugurlu N, Toklu Y, ÇIçek M, Boral B, Sener B et al (2020) Relationship between stages of diabetic retinopathy and levels of brain-derived neurotrophic factor in aqueous humor and serum. Retina 40(1):121–5

    Article  CAS  Google Scholar 

  9. Liu Y, Tao L, Fu X, Zhao Y, Xu X (2013) BDNF protects retinal neurons from hyperglycemia through the TrkB/ERK/MAPK pathway. Mol Med Rep 7(6):1773–1778

    Article  PubMed  CAS  Google Scholar 

  10. Ola MS, Nawaz MI, El-Asrar AA, Abouammoh M, Alhomida AS (2013) Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats. Cell Mol Neurobiol 33(3):359–367

    Article  CAS  PubMed  Google Scholar 

  11. Afarid M, Namvar E, Sanie-Jahromi F (2020) Diabetic retinopathy and BDNF: a review on its molecular basis and clinical applications. J Ophthalmol 2020:1–7

    Google Scholar 

  12. Afarid M, Torabi-Nami M, Zare B (2016) Neuroprotective and restorative effects of the brain-derived neurotrophic factor in retinal diseases. J Neurol Sci 363:43–50

    Article  CAS  PubMed  Google Scholar 

  13. Afarid M, Torabi-Nami M, Nemati A, Khosravi A, Malekzadeh M (2015) Brain-derived neurotrophic factor in patients with advanced age-related macular degeneration. Int J ophthalmol 8(5):991

    PubMed  PubMed Central  Google Scholar 

  14. Seki M, Tanaka T, Nawa H, Usui T, Fukuchi T, Ikeda K et al (2004) Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells. Diabetes 53(9):2412–2419

    Article  CAS  PubMed  Google Scholar 

  15. Osborne A, Khatib TZ, Songra L, Barber AC, Hall K, Kong GY et al (2018) Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. Cell Death Dis 9(10):1–18

    Article  CAS  Google Scholar 

  16. Ko M-L, Hu D-N, Ritch R, Sharma S, Chen C-F (2001) Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 305(2):139–142

    Article  CAS  PubMed  Google Scholar 

  17. Domenici L, Origlia N, Falsini B, Cerri E, Barloscio D, Fabiani C et al (2014) Rescue of retinal function by BDNF in a mouse model of glaucoma. PloS one 9(12):e115579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Shuto T, Horie H, Hikawa N, Sango K, Tokashiki A, Murata H et al (2001) IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration. NeuroReport 12(5):1081–1085

    Article  CAS  PubMed  Google Scholar 

  19. Sendtner M, Stöckli K, Thoenen H (1992) Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. J Cell Biol 118(1):139–148

    Article  CAS  PubMed  Google Scholar 

  20. Ju W-K, Lee M-Y, Hofmann H-D, Kirsch M, Chun M-H (1999) Expression of CNTF in Müller cells of the rat retina after pressure-induced ischemia. NeuroReport 10(2):419–422

    Article  CAS  PubMed  Google Scholar 

  21. Li R, Wen R, Banzon T, Maminishkis A, Miller SS (2011) CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PloS one 6(9):e23148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Beltran W, Rohrer H, Aguirre GD (2005) Immunolocalization of ciliary neurotrophic factor receptor α (CNTFRα) in mammalian photoreceptor cells. Mole Vis 11:232

    CAS  Google Scholar 

  23. Wahlin KJ, Campochiaro PA, Zack DJ, Adler R (2000) Neurotrophic factors cause activation of intracellular signaling pathways in Muller cells and other cells of the inner retina, but not photoreceptors. Invest Ophthalmol Vis Sci 41(3):927–936

    CAS  PubMed  Google Scholar 

  24. Fuhrmann S, Kirsch M, Heller S, Rohrer H, Hofmann HD (1998) Differential regulation of ciliary neurotrophic factor receptor-α expression in all major neuronal cell classes during development of the chick retina. J Comp Neurol 400(2):244–254

    Article  CAS  PubMed  Google Scholar 

  25. Valter K, Bisti S, Stone J (2003) Location of CNTFRα on outer segments: evidence of the site of action of CNTF in rat retina. Brain Res 985(2):169–175

    Article  CAS  PubMed  Google Scholar 

  26. Seydewitz V, Rothermel A, Fuhrmann S, Schneider A, DeGrip WJ, Layer PG et al (2004) Expression of CNTF receptor-α in chick violet-sensitive cones with unique morphologic properties. Invest Ophthalmol Vis Sci 45(2):655–661

    Article  PubMed  Google Scholar 

  27. Van Adel B, Arnold J, Phipps J, Doering L, Ball A (2005) Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal glia in vivo. J Neurobiol 63(3):215–234

    Article  PubMed  CAS  Google Scholar 

  28. Wen R, Song Y, Kjellstrom S, Tanikawa A, Liu Y, Li Y et al (2006) Regulation of rod phototransduction machinery by ciliary neurotrophic factor. J Neurosci 26(52):13523–13530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weise J, Isenmann S, Klöcker N, Kügler S, Hirsch S, Gravel C et al (2000) Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiol Dis 7(3):212–223

    Article  CAS  PubMed  Google Scholar 

  30. Li Y, Tao W, Luo L, Huang D, Kauper K, Stabila P et al (2010) CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PloS one 5(3):e9495

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Jo S, Wang E, Benowitz L (1999) Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience 89(2):579–591

    Article  CAS  PubMed  Google Scholar 

  32. Leibinger M, Müller A, Andreadaki A, Hauk TG, Kirsch M, Fischer D (2009) Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 29(45):14334–14341

    Article  PubMed  PubMed Central  Google Scholar 

  33. Iulia C, Ruxandra T, Costin L-B, Liliana-Mary V (2017) Citicoline—a neuroprotector with proven effects on glaucomatous disease. Romanian J ophthalmol 61(3):152

    Article  Google Scholar 

  34. Zerbini G, Bandello F, Lattanzio R, Gabellini D, Zucchiatti I, Spinello A et al (2015) In vivo evaluation of retinal and choroidal structure in a mouse model of long-lasting diabetes. Effect of topical treatment with citicoline. J Ocul Dis Ther 3:1–8

    Article  Google Scholar 

  35. Rejdak R, Toczołowski J, Kurkowski J, Kamiński M, Rejdak K, Stelmasiak Z et al (2003) Oral citicoline treatment improves visual pathway function in glaucoma. Med Sci Monit 9(3):PI24–PI8

    CAS  PubMed  Google Scholar 

  36. Rejdak R, Toczołowski J, Solski J, Duma D, Grieb P (2002) Citicoline treatment increases retinal dopamine content in rabbits. Ophthalmic Res 34(3):146–149

    Article  CAS  PubMed  Google Scholar 

  37. Schuettauf F, Rejdak R, Thaler S, Bolz S, Lehaci C, Mankowska A et al (2006) Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res 83(5):1128–1134

    Article  CAS  PubMed  Google Scholar 

  38. Park CH, Kim YS, Noh HS, Cheon EW, Yang YA, Yoo JM et al (2005) Neuroprotective effect of citicoline against KA-induced neurotoxicity in the rat retina. Exp Eye Res 81(3):350–358

    Article  CAS  PubMed  Google Scholar 

  39. Parisi V, Manni G, Colacino G, Bucci MG (1999) Cytidine-5′-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology 106(6):1126–1134

    Article  CAS  PubMed  Google Scholar 

  40. Parisi V (2005) Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-5′-diphosphocholine (citicoline): a study of 8 years of follow-up. Doc Ophthalmol 110(1):91–102

    Article  PubMed  Google Scholar 

  41. Parisi V, Coppola G, Centofanti M, Oddone F, Angrisani AM, Ziccardi L et al (2008) Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res 173:541–554

    Article  CAS  PubMed  Google Scholar 

  42. Johnson K, Brooks B, Cohen J, Ford C, Goldstein J, Lisak R et al (1998) Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 50(3):701–708

    Article  CAS  PubMed  Google Scholar 

  43. Johnson K, Brooks B, Cohen J, Ford C, Goldstein J, Lisak R et al (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 45(7):1268–1276

    Article  CAS  PubMed  Google Scholar 

  44. Dhib-Jalbut S (2003) Glatiramer acetate (Copaxone®) therapy for multiple sclerosis. Pharmacol Ther 98(2):245–255

    Article  CAS  PubMed  Google Scholar 

  45. Bakalash S, Kessler A, Mizrahi T, Nussenblatt R, Schwartz M (2003) Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma. Invest Ophthalmol Vis Sci 44(8):3374–3381

    Article  PubMed  Google Scholar 

  46. Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler LA et al (2001) Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci 98(6):3398–3403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M et al (2000) T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci 97(13):7446–7451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Abrishami M, Khalifeh M, Shoayb M, Abrishami M (2011) Therapeutic effects of high-dose intravenous prednisolone in methanol-induced toxic optic neuropathy. J Ocul Pharmacol Ther 27(3):261–263

    Article  CAS  PubMed  Google Scholar 

  49. Doonan F, O’Driscoll C, Kenna P, Cotter TG (2011) Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel. J Neurochem 118(5):915–927

    Article  CAS  PubMed  Google Scholar 

  50. Posthumus R (1952) The use and the possibilities of progesterone in the treatment of glaucoma. Ophthalmologica 124(1):17–25

    Article  CAS  PubMed  Google Scholar 

  51. Toris CB, Camras CB, Yablonski ME (1999) Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients. Am J Ophthalmol 128(1):8–14

    Article  CAS  PubMed  Google Scholar 

  52. Galanopoulos A, Goldberg I (2009) Clinical efficacy and neuroprotective effects of brimonidine in the management of glaucoma and ocular hypertension. Clin ophthalmol (Auckl NZ) 3:117

    CAS  Google Scholar 

  53. Wheeler LA, Gil DW, WoldeMussie E (2001) Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol 45:S290–S294

    Article  PubMed  Google Scholar 

  54. Bylund DB, Chacko DM (1999) Characterization of α2 adrenergic receptor subtypes in human ocular tissue homogenates. Invest Ophthalmol Vis Sci 40(10):2299–2306

    CAS  PubMed  Google Scholar 

  55. Wheeler L, Lai R, Woldemussie E (1999) From the lab to the clinic: activation of an alpha-2 agonist pathway is neuroprotective in models of retinal and optic nerve injury. Eur J Ophthalmol 9((1_suppl)):17–21

    Article  Google Scholar 

  56. Hosseinzadeh H, Nassiri-Asl M (2014) Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Invest 37(9):783–788

    Article  CAS  PubMed  Google Scholar 

  57. Kim H, Kong H, Choi B, Yang Y, Kim Y, Lim MJ et al (2005) Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease. Pharm Res 22(9):1499–1509

    Article  CAS  PubMed  Google Scholar 

  58. Pescosolido N, Librando A (2010) Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients. La Clinica terapeutica 161(3):e81–e85

    CAS  PubMed  Google Scholar 

  59. Vetrugno M, Uva MG, Russo V, Iester M, Ciancaglini M, Brusini P et al (2012) Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther 28(5):536–541

    Article  CAS  PubMed  Google Scholar 

  60. Nakayama M, Aihara M, Chen Y-N, Araie M, Tomita-Yokotani K, Iwashina T (2011) Neuroprotective effects of flavonoids on hypoxia-, glutamate-, and oxidative stress–induced retinal ganglion cell death. Mol Vision 17:1784

    CAS  Google Scholar 

  61. Na J-Y, Kim S, Song K, Kwon J (2014) Rutin alleviates prion peptide-induced cell death through inhibiting apoptotic pathway activation in dopaminergic neuronal cells. Cell Mol Neurobiol 34(7):1071–1079

    Article  CAS  PubMed  Google Scholar 

  62. Ola MS, Ahmed MM, Ahmad R, Abuohashish HM, Al-Rejaie SS, Alhomida AS (2015) Neuroprotective effects of rutin in streptozotocin-induced diabetic rat retina. J Mol Neurosci 56(2):440–448

    Article  CAS  PubMed  Google Scholar 

  63. Rusciano D, Pezzino S, Mutolo MG, Giannotti R, Librando A, Pescosolido N (2017) Neuroprotection in glaucoma: old and new promising treatments. Adv Pharmacol Sci 2017:1–19

    Google Scholar 

  64. Thibault O, Gant JC, Landfield PW (2007) Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: minding the store. Aging Cell 6(3):307–317

    Article  CAS  PubMed  Google Scholar 

  65. Takano Y, Ohguro H, Dezawa M, Ishikawa H, Yamazaki H, Ohguro I et al (2004) Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse. Biochem Biophys Res Commun 313(4):1015–1022

    Article  CAS  PubMed  Google Scholar 

  66. Krishnan J, Malathi R (2018) Effect of L, T and N-Type Calcium channels on retinal ganglion cells. Mater Today Proc 5(1):1929–1935

    Article  CAS  Google Scholar 

  67. Ganekal S, Dorairaj S, Jhanji V, Kudlu K (2014) Effect of topical calcium channel blockers on intraocular pressure in steroid-induced glaucoma. J Curr Glaucoma Pract 8(1):15

    Article  PubMed  PubMed Central  Google Scholar 

  68. Araie M, Mayama C (2011) Use of calcium channel blockers for glaucoma. Prog Retin Eye Res 30(1):54–71

    Article  CAS  PubMed  Google Scholar 

  69. Luo D, Fan Y, Xu X (2012) The effects of aminoguanidine on retinopathy in STZ-induced diabetic rats. Bioorg Med Chem Lett 22(13):4386–4390

    Article  CAS  PubMed  Google Scholar 

  70. Neufeld AH, Sawada A, Becker B (1999) Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci 96(17):9944–9948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Falsini B, Piccardi M, Minnella A, Savastano C, Capoluongo E, Fadda A et al (2010) Influence of saffron supplementation on retinal flicker sensitivity in early age-related macular degeneration. Invest Ophthalmol Vis Sci 51(12):6118–6124

    Article  PubMed  Google Scholar 

  72. Riazi A, Panahi Y, Alishiri AA, Hosseini MA, Zarchi AAK, Sahebkar A (2017) The impact of saffron (Crocus sativus) supplementation on visual function in patients with dry age-related macular degeneration. Ital J Med 11(2):196–201

    Google Scholar 

  73. Di Marco S, Carnicelli V, Franceschini N, Di Paolo M, Piccardi M, Bisti S et al (2019) Saffron: a multitask neuroprotective agent for retinal degenerative diseases. Antioxidants 8(7):224

    Article  PubMed Central  CAS  Google Scholar 

  74. Saini R (2011) Coenzyme Q10: the essential nutrient. J Pharm Bioallied Sci 3(3):466–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Spindler M, Beal MF, Henchcliffe C (2009) Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat 5:597

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Somayajulu M, McCarthy S, Hung M, Sikorska M, Borowy-Borowski H, Pandey S (2005) Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by Coenzyme Q10. Neurobiol Dis 18(3):618–627

    Article  CAS  PubMed  Google Scholar 

  77. Schmelzer C, Lindner I, Rimbach G, Niklowitz P, Menke T, Döring F (2008) Functions of coenzyme Q10 in inflammation and gene expression. BioFactors 32(1–4):179–183

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the directors of Shiraz University of Medical Sciences for supporting this research.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Poostchi Ophthalmology Research Center, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran

    Mehrdad Afarid & Fatemeh Sanie-Jahromi

Authors
  1. Mehrdad Afarid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Sanie-Jahromi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MA and FS-J were involved in conception and design of the study, acquisition of documents, interpretation of available studies, drafting the manuscript and final revision.

Corresponding author

Correspondence to Fatemeh Sanie-Jahromi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Afarid, M., Sanie-Jahromi, F. Potential neuroprotective biomolecules in ophthalmology. Int Ophthalmol 41, 1103–1109 (2021). https://doi.org/10.1007/s10792-020-01634-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-020-01634-8

Keywords

Search

Navigation