Neuroprotective effect of latanoprost on rat retinal ganglion cells

  • Hideyo Kudo
  • Toru Nakazawa
  • Masahiko Shimura
  • Hidetoshi Takahashi
  • Nobuo Fuse
  • Kenji Kashiwagi
  • Makoto Tamai
Laboratory Investigation



To investigate the neuroprotective effect of intravitreal administration of latanoprost on retinal ganglion cell (RGC) damage induced by N-methyl-D-aspartic acid (NMDA) or optic nerve axotomy.


Using Sprague-Dawley rats, retinal ganglion cell damage was induced by either intravitreal administration of NMDA or optic nerve axotomy. Latanoprost at doses of 0.03, 0.3, 3, 30 and 300 pmol was administered intravitreally before NMDA injection or optic nerve axotomy. Retinal damage was evaluated by counting the number of surviving RGCs retrogradely labeled with fluorogold under the microscope.


Seven days after the NMDA injury, the number of surviving RGCs was significantly increased at doses of more than 30 pmol atanoprost (846±178 cells/mm2 P=0.0166) compared with vehicle control (556±122 cells/mm2). Ten days after the optic nerve axotomy, the number of surviving RGC was significantly increased even at a dose of 0.3 pmol (815±239 cells/mm2, P=0.0359) compared with control (462±75 cells/mm2).


Intravitreal administration of latanoprost has a neuroprotective effect on rat RGC damage induced by either NMDA or optic nerve axotomy, while its pharmacological features are different.


Neuroprotection Retinal ganglion cell Axotomy Glaucoma Latanoprost N-Methyl-D-aspartic acid 



We thank Haicheng She, MD, PhD (Massachusetts eye and ear infirmary, Boston, Mass., USA) for editing our manuscript.


  1. 1.
    Abramovitz M, Boie Y, Nguyen T, Rushmore TH, Bayne MA, Metters KM, Slipetz DM, Grygorczyk R (1994) Cloning and expression of a cDNA for the human prostanoid FP receptor. J Biol Chem 269:2632–2636PubMedGoogle Scholar
  2. 2.
    Ahmed F, Brown KM, Stephan DA, Morrison JC, Johnson EC, Tomarev SI (2004) Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Invest Ophthalmol Vis Sci 45:1247–1258PubMedCrossRefGoogle Scholar
  3. 3.
    Ahmed F, Torrado M, Johnson E, Morrison J, Tomarev SI (2001) Changes in mRNA levels of the Myoc/Tigr gene in the rat eye after experimental elevation of intraocular pressure or optic nerve transection. Invest Ophthalmol Vis Sci 42:3165–3172PubMedGoogle Scholar
  4. 4.
    Akiyama H, Nakazawa T, Shimura M, Tomita H, Tamai M (2002) Presence of mitogen-activated protein kinase in retinal Muller cells and its neuroprotective effect ischemia-reperfusion injury. Neuroreport 13:2103–2107PubMedCrossRefGoogle Scholar
  5. 5.
    Alm A, Stjernschantz J (1995) Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology 102:1743–1752PubMedGoogle Scholar
  6. 6.
    Ansari HR, Kaddour-Djebbar I, Abdel-Latif AA (2004) Effects of prostaglandin F2alpha, latanoprost and carbachol on phosphoinositide turnover, MAP kinases, myosin light chain phosphorylation and contraction and functional existence and expression of FP receptors in bovine iris sphincter. Exp Eye Res 78:285–296PubMedCrossRefGoogle Scholar
  7. 7.
    Araie M, Takase M, Sakai Y, Ishii Y, Yokoyama Y, Kitagawa M (1982) Beta-adrenergic blockers: ocular penetration and binding to the uveal pigment. Jpn J Ophthalmol 26:248–263PubMedGoogle Scholar
  8. 8.
    Bautista RD (1999) Glaucomatous neurodegeneration and the concept of neuroprotection. Int Ophthalmol Clin 39:57–70PubMedCrossRefGoogle Scholar
  9. 9.
    Chen CC, Koda RT, Shackleton M (1988) The ocular distribution of bunolol in the eyes of albino and pigmented rabbits. J Ocul Pharmacol 4:37–42PubMedCrossRefGoogle Scholar
  10. 10.
    Drago F, Valzelli S, Emmi I, Marino A, Scalia CC, Marino V (2001) Latanoprost exerts neuroprotective activity in vitro and in vivo. Exp Eye Res 72:479–486PubMedCrossRefGoogle Scholar
  11. 11.
    Endo S, Tomita H, Ishiguro S, Tamai M (2002) Effect of betaxolol on aspartate aminotransferase activity in hypoxic rat retina in vitro. Jpn J Pharmacol 90:121–124PubMedCrossRefGoogle Scholar
  12. 12.
    Fujio N, Kusumoto N, Odomi M (1994) Ocular distribution of carteolol after single and repeated ocular instillation in pigmented rabbits. Acta Ophthalmol (Copenh) 72:688–693Google Scholar
  13. 13.
    Goto W, Ota T, Morikawa N, Otori Y, Hara H, Kawazu K, Miyawaki N, Tano Y (2002) Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina. Brain Res 958:10–19PubMedCrossRefGoogle Scholar
  14. 14.
    Hejkal TW, Camras CB (1999) Prostaglandin analogs in the treatment of glaucoma. Semin Ophthalmol 14:114–123PubMedCrossRefGoogle Scholar
  15. 15.
    Ishii K, Tomidokoro A, Nagahara M, Tamaki Y, Kanno M, Fukaya Y, Araie M (2001) Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans. Invest Ophthalmol Vis Sci 42:2957–2963PubMedGoogle Scholar
  16. 16.
    Kashiwagi K, Iizuka Y, Tsukahara S (2002) Neuroprotective effects of nipradilol on purified cultured retinal ganglion cells. J Glaucoma 11:231–238PubMedCrossRefGoogle Scholar
  17. 17.
    Kashiwagi K, Kanai N, Tsuchida T, Suzuki M, Iizuka Y, Tanaka Y, Tsukahara S (2002) Comparison between isopropyl unoprostone and latanoprost by prostaglandin E(2)induction, affinity to prostaglandin transporter, and intraocular metabolism. Exp Eye Res 74:41–49PubMedCrossRefGoogle Scholar
  18. 18.
    Kaushik S, Pandav SS, Ram J (2003) Neuroprotection in glaucoma. J Postgrad Med 49:90–95PubMedCrossRefGoogle Scholar
  19. 19.
    Koeberle PD, Ball AK (1998) Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res 38:1505–1515PubMedCrossRefGoogle Scholar
  20. 20.
    Kunapuli P, Lawson JA, Rokach JA, Meinkoth JL, FitzGerald GA (1998) Prostaglandin F2alpha (PGF2alpha) and the isoprostane, 8, 12-iso-isoprostane F2alpha-III, induce cardiomyocyte hypertrophy. Differential activation of downstream signaling pathways. J Biol Chem 273:22442–22452PubMedCrossRefGoogle Scholar
  21. 21.
    Levin LA (2003) Retinal ganglion cells and neuroprotection for glaucoma. Surv Ophthalmol 48:S21–S24PubMedCrossRefGoogle Scholar
  22. 22.
    Matsuo T, Cynader MS (1992) Localisation of prostaglandin F2 alpha and E2 binding sites in the human eye. Br J Ophthalmol 76:210–213PubMedCrossRefGoogle Scholar
  23. 23.
    McCullough L, Wu L, Haughey N, Liang X, Hand T, Wang Q, Breyer RM, Andreasson K (2004) Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. J Neurosci 24:257–268PubMedCrossRefGoogle Scholar
  24. 24.
    Melamed S (2002) Neuroprotective properties of a synthetic docosanoid, unoprostone isopropyl: clinical benefits in the treatment of glaucoma. Drugs Exp Clin Res 28:63–73PubMedGoogle Scholar
  25. 25.
    Mizuno K, Koide T, Saito N, Fujii M, Nagahara M, Tomidokoro A, Tamaki Y, Araie M (2002) Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. Invest Ophthalmol Vis Sci 43:3243–3250PubMedGoogle Scholar
  26. 26.
    Mizuno K, Koide T, Yoshimura M, Araie M (2001) Neuroprotective effect and intraocular penetration of nipradilol, a beta-blocker with nitric oxide donative action. Invest Ophthalmol Vis Sci 42:688–694PubMedGoogle Scholar
  27. 27.
    Nakazawa T, Nakano I, Sato M, Nakamura T, Tamai M, Mori N (2002) Comparative expression profiles of Trk receptors and Shc-related phosphotyrosine adapters during retinal development: potential roles of N-Shc/ShcC in brain-derived neurotrophic factor signal transduction and modulation. J Neurosci Res 68:668–680PubMedCrossRefGoogle Scholar
  28. 28.
    Nakazawa T, Shimura M, Tomita H, Akiyama H, Yoshioka Y, Kudou H, Tamai M (2003) Intrinsic activation of PI3K/Akt signaling pathway and its neuroprotective effect against retinal injury. Curr Eye Res 26:55–63PubMedCrossRefGoogle Scholar
  29. 29.
    Nakazawa T, Tamai M, Mori N (2002) Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3K signaling pathways. Invest Ophthalmol Vis Sci 43:3319–3326PubMedGoogle Scholar
  30. 30.
    Nakazawa T, Tomita H, Yamaguchi K, Sato Y, Shimura M, Kuwahara S, Tamai M (2002) Neuroprotective effect of nipradilol on axotomized rat retinal ganglion cells. Curr Eye Res 24:114–122PubMedCrossRefGoogle Scholar
  31. 31.
    Osborne NN, Cazevieille C, Carvalho AL, Larsen AK, DeSantis L (1997) In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent. Brain Res 751:113–123PubMedCrossRefGoogle Scholar
  32. 32.
    Quigley HA (1996) Number of people with glaucoma worldwide. Br J Ophthalmol 80:389–393PubMedCrossRefGoogle Scholar
  33. 33.
    Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP (2004) Global data on visual impairment in the year 2002. Bull World Health Org 82:844–851PubMedGoogle Scholar
  34. 34.
    Schlotzer-Schrehardt U, Zenkel M, Nusing RM (2002) Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues. Invest Ophthalmol Vis Sci 43:1475–1487PubMedGoogle Scholar
  35. 35.
    Vorwerk CK, Hyman BT, Miller JW, Husain D, Zurakowski D, Huang PL, Fishman MC, Dreyer EB (1997) The role of neuronal and endothelial nitric oxide synthase in retinal excitotoxicity. Invest Ophthalmol Vis Sci 38: 2038–2044PubMedGoogle Scholar
  36. 36.
    Wheeler LA, Gil DW, WoldeMussie E (2001) Role of alpha–2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol 45: S290–294; discussion S295–S296PubMedCrossRefGoogle Scholar
  37. 37.
    Wheeler LA, 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:S17–S21PubMedGoogle Scholar
  38. 38.
    Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N (2003) Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 22:465–481PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Hideyo Kudo
    • 1
  • Toru Nakazawa
    • 1
  • Masahiko Shimura
    • 1
    • 2
  • Hidetoshi Takahashi
    • 1
  • Nobuo Fuse
    • 1
  • Kenji Kashiwagi
    • 3
  • Makoto Tamai
    • 1
  1. 1.Department of OphthalmologyTohoku University School of MedicineSendaiJapan
  2. 2.Department of OphthalmologyNTT East Japan Tohoku HospitalSendaiJapan
  3. 3.Department of Ophthalmology, University of YamanashiFaculty of MedicineTamahoJapan

Personalised recommendations