Advertisement

Exogenous modulation of intrinsic optic nerve neuroprotective activity

  • Sinisa D. GrozdanicEmail author
  • Tatjana Lazic
  • Markus H. Kuehn
  • Matthew M. Harper
  • Randy H. Kardon
  • Young H. Kwon
  • Erin B. Lavik
  • Donald S. Sakaguchi
Basic Science

Abstract

Background

To characterize the molecular and functional status of the rat retina and optic nerve after acute elevation of intraocular pressure (IOP).

Methods

Retinal ischemia was induced in rats by increasing the IOP (110 mmHg/60 minutes). Microarray analysis, quantitative RT-PCR (qRT-PCR) and immunohistochemistry were used to characterize retinal tissue. PLGA microspheres containing neurotrophic factors (BDNF, GDNF, or CNTF) or empty microspheres were injected into the vitreous of operated animals 1 day after elevation of IOP. Pupil light reflex (PLR) parameters and electroretinograms (ERG) were monitored at multiple time points during the 60-day postoperative recovery period.

Results

Molecular analysis showed a significant intrinsic up-regulation of CNTF at 10 and 25 days after induction of the acute ocular hypertension (p = 0.0067). Molecular tissue analysis of GDNF and its receptors (GDNFR1, GDNFR2), and BDNF and its receptor (trkB) showed no change in expression. Animals that received CNTF microspheres had no significant functional recovery compared to animals which received blank microspheres (p > 0.05). Animals that received GDNF or BDNF microspheres showed significant PLR recovery (p < 0.05 and p < 0.001 respectively) compared to non-treated animals.

Conclusions

Continuous release of neurotrophic growth factors (NGFs) significantly protects optic nerve function in the experimental model of retinal ischemia observed by PLR analysis.

Keywords

Neuroprotection Retina BDNF GDNF CNTF 

Notes

Acknowledgements

We would like to thank Dr Sally Hildreth and Mr Jeff Orasky for the help with experiment performance. This work was supported in part by Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Grant C3919R, The Glaucoma Foundation, NY, an unrestricted grant from Research to Prevent Blindness (Dept. of Ophthalmology, University of Iowa), NIH NS044007, NIH EY019485, NIH EY019294 and ISU Biotechnology Carver Trust Grant.

References

  1. 1.
    Adachi M, Takahashi K, Nishikawa M, Miki H, Uyama M (1996) High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats. Graefes Arch Clin Exp Ophthalmol 234:445–451CrossRefPubMedGoogle Scholar
  2. 2.
    Hughes WF (1991) Quantitation of ischemic damage in the rat retina. Exp Eye Res 53:573–582CrossRefPubMedGoogle Scholar
  3. 3.
    Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18:39–57CrossRefPubMedGoogle Scholar
  4. 4.
    Takahashi H, Goto T, Shoji T, Tanito M, Park M, Chihara E (2006) Diabetes-associated retinal nerve fiber damage evaluated with scanning laser polarimetry. Am J Ophthalmol 142:88–94CrossRefPubMedGoogle Scholar
  5. 5.
    Ko ML, Hu DN, Ritch R, Sharma SC (2000) The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. Invest Ophthalmol Vis Sci 41:2967–2971PubMedGoogle Scholar
  6. 6.
    Ko ML, Hu DN, Ritch R, Sharma SC, Chen CF (2001) Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 305:139–142CrossRefPubMedGoogle Scholar
  7. 7.
    Martin KR, Quigley HA, Zack DJ, Levkovitch-Verbin H, Kielczewski J, Valenta D, Baumrind L, Pease ME, Klein RL, Hauswirth WW (2003) Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 44:4357–4365CrossRefPubMedGoogle Scholar
  8. 8.
    Ward MS, Khoobehi A, Lavik EB, Langer R, Young MJ (2007) Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres. J Pharm Sci 96:558–568CrossRefPubMedGoogle Scholar
  9. 9.
    Ji JZ, Elyaman W, Yip HK, Lee VW, Yick LW, Hugon J, So KF (2004) CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur J Neurosci 19:265–272CrossRefPubMedGoogle Scholar
  10. 10.
    LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH (1992) Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci U S A 89:11249–11253CrossRefPubMedGoogle Scholar
  11. 11.
    LaVail MM, Yasumura D, Matthes MT, Lau-Villacorta C, Unoki K, Sung CH, Steinberg RH (1998) Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 39:592–602PubMedGoogle Scholar
  12. 12.
    Carwile ME, Culbert RB, Sturdivant RL, Kraft TW (1998) Rod outer segment maintenance is enhanced in the presence of bFGF, CNTF and GDNF. Exp Eye Res 66:791–805CrossRefPubMedGoogle Scholar
  13. 13.
    Frasson M, Picaud S, Leveillard T, Simonutti M, Mohand-Said S, Dreyfus H, Hicks D, Sabel J (1999) Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse. Invest Ophthalmol Vis Sci 40:2724–2734PubMedGoogle Scholar
  14. 14.
    Thanos C, Emerich D (2005) Delivery of neurotrophic factors and therapeutic proteins for retinal diseases. Expert Opin Biol Ther 5:1443–1452CrossRefPubMedGoogle Scholar
  15. 15.
    Barnett NL, Grozdanic SD (2004) Glutamate transporter localization does not correspond to the temporary functional recovery and late degeneration after acute ocular ischemia in rats. Exp Eye Res 79:513–524CrossRefPubMedGoogle Scholar
  16. 16.
    Grozdanic SD, Kwon YH, Sakaguchi DS, Kardon RH, Sonea IM (2004) Functional evaluation of retina and optic nerve in the rat model of chronic ocular hypertension. Exp Eye Res 79:75–83CrossRefPubMedGoogle Scholar
  17. 17.
    Grozdanic SD, Sakaguchi DS, Kwon YH, Kardon RH, Sonea IM (2003) Functional characterization of retina and optic nerve after acute ocular ischemia in rats. Invest Ophthalmol Vis Sci 44:2597–2605CrossRefPubMedGoogle Scholar
  18. 18.
    Fu K, Harrell R, Zinski K, Um C, Jaklenec A, Frazier J, Lotan N, Burke P, Klibanov AM, Langer R (2003) A potential approach for decreasing the burst effect of protein from PLGA microspheres. J Pharm Sci 92:1582–1591CrossRefPubMedGoogle Scholar
  19. 19.
    Lavik EB, Hrkach JS, Lotan N, Nazarov R, Langer R (2001) A simple synthetic route to the formation of a block copolymer of poly(lactic-co-glycolic acid) and polylysine for the fabrication of functionalized, degradable structures for biomedical applications. J Biomed Mater Res 58:291–294CrossRefPubMedGoogle Scholar
  20. 20.
    Ford MC, Bertram JP, Hynes SR, Michaud M, Li Q, Young M, Segal SS, Madri JA, Lavik EB (2006) A macroporous hydrogel for the co-culture of neural progenitor and endothelial cells to form functional vascular networks in vivo. Proc Natl Acad Sci U S A 103:2512–2517CrossRefPubMedGoogle Scholar
  21. 21.
    Hermanson GT (1996) Bioconjugate Techniques. Academic Press, San DiegoGoogle Scholar
  22. 22.
    Nkansah MK, Tzeng SY, Holdt AM, Lavik EB (2008) Poly(lactic-co-glycolic acid) nanospheres and microspheres for short-and long-term delivery of bioactive ciliary neurotrophic factor. Biotechnol Bioeng 100:1010–1019CrossRefPubMedGoogle Scholar
  23. 23.
    Grozdanic S, Sakaguchi DS, Kwon YH, Kardon RH, Sonea IM (2002) Characterization of the pupil light reflex, electroretinogram and tonometric parameters in healthy rat eyes. Curr Eye Res 25:69–78CrossRefPubMedGoogle Scholar
  24. 24.
    Grozdanic SD, Betts DM, Sakaguchi DS, Allbaugh RA, Kwon YH, Kardon RH (2003) Laser-induced mouse model of chronic ocular hypertension. Invest Ophthalmol Vis Sci 44:4337–4346CrossRefPubMedGoogle Scholar
  25. 25.
    Grozdanic SD, Betts DM, Sakaguchi DS, Kwon YH, Kardon RH, Sonea IM (2003) Temporary elevation of the intraocular pressure by cauterization of vortex and episcleral veins in rats causes functional deficits in the retina and optic nerve. Exp Eye Res 77:27–33CrossRefPubMedGoogle Scholar
  26. 26.
    Grozdanic SD, Ast AM, Lazic T, Kwon YH, Kardon RH, Sonea IM, Sakaguchi DS (2006) Morphological integration and functional assessment of transplanted neural progenitor cells in healthy and acute ischemic rat eyes. Exp Eye Res 82:597–607CrossRefPubMedGoogle Scholar
  27. 27.
    Wen R, Song Y, Cheng T, Matthes MT, Yasumura D, LaVail MM, Steinberg RH (1995) Injury-induced upregulation of bFGF and CNTF mRNAS in the rat retina. J Neurosci 15:7377–7385PubMedGoogle Scholar
  28. 28.
    Cao W, Wen R, Li F, Lavail MM, Steinberg RH (1997) Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina. Exp Eye Res 65:241–248CrossRefPubMedGoogle Scholar
  29. 29.
    Liu C, Peng M, Laties AM, Wen R (1998) Preconditioning with bright light evokes a protective response against light damage in the rat retina. J Neurosci 18:1337–1344PubMedGoogle Scholar
  30. 30.
    Ju WK, Lee MY, Hofmann HD, Kirsch M, Chun MH (1999) Expression of CNTF in Muller cells of the rat retina after pressure-induced ischemia. Neuroreport 10:419–422CrossRefPubMedGoogle Scholar
  31. 31.
    Chun MH, Ju WK, Kim KY, Lee MY, Hofmann HD, Kirsch M, Oh SJ (2000) Upregulation of ciliary neurotrophic factor in reactive Muller cells in the rat retina following optic nerve transection. Brain Res 868:358–362CrossRefPubMedGoogle Scholar
  32. 32.
    Ju WK, Kim KY, Lee MY, Hofmann HD, Kirsch M, Cha JH, Oh SJ, Chun MH (2000) Up-regulated CNTF plays a protective role for retrograde degeneration in the axotomized rat retina. Neuroreport 11:3893–3896CrossRefPubMedGoogle Scholar
  33. 33.
    Sarup V, Patil K, Sharma SC (2004) Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina. Brain Res 1013:152–158CrossRefPubMedGoogle Scholar
  34. 34.
    Harada C, Harada T, Quah HM, Maekawa F, Yoshida K, Ohno S, Wada K, Parada LF, Tanaka K (2003) Potential role of glial cell line-derived neurotrophic factor receptors in Muller glial cells during light-induced retinal degeneration. Neuroscience 122:229–235CrossRefPubMedGoogle Scholar
  35. 35.
    Harada T, Harada C, Nakayama N, Okuyama S, Yoshida K, Kohsaka S, Matsuda H, Wada K (2000) Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26:533–541CrossRefPubMedGoogle Scholar
  36. 36.
    Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, Mamada H, Tanaka K, Parada LF, Wada K (2002) Microglia-Muller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J Neurosci 22:9228–9236PubMedGoogle Scholar
  37. 37.
    Beltran WA, Wen R, Acland GM, Aguirre GD (2007) Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina. Exp Eye Res 84:753–771CrossRefPubMedGoogle Scholar
  38. 38.
    Zeiss CJ, Allore HG, Towle V, Tao W (2006) CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Exp Eye Res 82:395–404CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sinisa D. Grozdanic
    • 1
    • 4
    Email author
  • Tatjana Lazic
    • 1
    • 4
  • Markus H. Kuehn
    • 3
    • 4
  • Matthew M. Harper
    • 1
    • 2
    • 4
  • Randy H. Kardon
    • 3
    • 4
  • Young H. Kwon
    • 3
  • Erin B. Lavik
    • 5
  • Donald S. Sakaguchi
    • 2
    • 4
  1. 1.Department of Veterinary Clinical Sciences, College of Veterinary MedicineIowa State UniversityAmesUSA
  2. 2.Department of Genetics, Development and Cell Biology and the Neuroscience ProgramIowa State UniversityAmesUSA
  3. 3.Department of Ophthalmology and Visual SciencesUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  4. 4.United States Veterans Affairs Center for the Prevention and Treatment of Visual LossVA Medical CenterIowa CityUSA
  5. 5.Department of Biomedical EngineeringCase Western Reserve UniversityClevelandUSA

Personalised recommendations