Cellular and Molecular Neurobiology

, Volume 32, Issue 3, pp 467–475

Protective Effects of Adeno-associated Virus Mediated Brain-derived Neurotrophic Factor Expression on Retinal Ganglion Cells in Diabetic Rats

  • Yan Gong
  • Zhan-Ping Chang
  • Ruo-Tong Ren
  • Shi-hui Wei
  • Huan-Fen Zhou
  • Xiao-fei Chen
  • Bao-ke Hou
  • Xin Jin
  • Mao-nian Zhang
Original Research


Adeno-associated virus vector plasmid carrying the expression cassette of brain-derived neurotrophic factor (BDNF), pAAV-BDNF, was constructed and packaged into recombinant adeno-associated virus (rAAV-BDNF). The rAAV-BDNF was intravitreally injected into streptzotocin (STZ)-induced diabetic Sprague–Dawley (SD) Rats. Data showed that over-expression of BDNF could increase alive retinal ganglion cell (RGC) number and improve its function in streptzotocin(STZ)-induced diabetic rats, which might be a new method to treat diabetic neuropathy and retinopathy.


Streptzotocin(STZ) Diabetic retinopathy Gene therapy Adeno-associated virus (AAV) Brain-derived neurotrophic factor (BDNF) 


  1. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM (1995) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374:450–453PubMedCrossRefGoogle Scholar
  2. Akhtar N, Akram M, Asif HM, Usmanghani K, Ali Shah SM, Ahmad Rao S, Uzair M, Shaheen G, Ahmad K (2011) Gene therapy: a review article. Fly1 J Med Plants Res 5(10):1812–1817Google Scholar
  3. Algan M, Ziegler O, Gehin P, Got I, Raspiller A, Weber M, Genton P, Saudax E, Drouin P (1989) Visual evoked potentials in diabetic patients. Diabetes Care 12:227–229PubMedCrossRefGoogle Scholar
  4. American Diabetes Association (2007) Diagnosis and classification of diabetes mellitus. Diabetes Care 30(Supp1):S42–S47CrossRefGoogle Scholar
  5. Baillart JP, L’examen FM (1954) Rapport à la Société d’Ophthalmologie de Paris. Bull Soc Ophthalmol Fr 4(Suppl):I–LXVIIGoogle Scholar
  6. Bloomgarden ZT (2008) Diabetic retinopathy. Diabetes Care 31:1080–1083PubMedCrossRefGoogle Scholar
  7. Bresnick GH, Korth K, Groo A, Palta M (1984) Electroretinographic oscillatory potentials predict progression of diabetic retinopathy. Preliminary report. Arch Ophthalmol 102:1307–1311PubMedCrossRefGoogle Scholar
  8. Caputo S, Di Leo MA, Falsini B, Ghirlanda G, Porciatti V, Minella A, Greco AV (1990) Evidence for early impairment of macular function with pattern ERG in type I diabetic patients. Diabetes Care 13:412–418PubMedCrossRefGoogle Scholar
  9. Center for disease control and prevention (2011) National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. U.S department of health and human services, Center for disease control and prevention, AtlantaGoogle Scholar
  10. Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet 351:28–31PubMedCrossRefGoogle Scholar
  11. Cobb WA, Morton HB (1953) A new component of the human electroretinogram. J Physiol (Lond) 123:36–37Google Scholar
  12. The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
  13. Di Leo MA, Falsini B, Caputo S, Ghirlanda G, Porciatti V, Greco AV (1990) Spatial frequency-selective losses with pattern electroretinogram in type 1 (insulin-dependent) diabetic patients without retinopathy. Diabetologia 33:726–730PubMedCrossRefGoogle Scholar
  14. Ewing FM, Deary IJ, Strachan MW, Frier BM (1998) Seeing beyond retinopathy in diabetes: electrophysiological and psychophysical abnormalities and alterations in vision. Endocr Rev 19:462–476PubMedCrossRefGoogle Scholar
  15. Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL (2007) Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des 13:2699–2712PubMedCrossRefGoogle Scholar
  16. Franchi A, Magni R, Lodigiani L, Cordella M (1987) VEP pattern after photostress: an index of macular function. Graefes Arch Clin Exp Ophthalmol 225:291–294PubMedCrossRefGoogle Scholar
  17. Giraldi A, Persson K, Werkstrom V, Alm P, Wagner G, Andersson KE (2001) Effects of diabetes on neurotransmission in rat vaginal smooth muscle. Int J Impot Res 13:58–66PubMedCrossRefGoogle Scholar
  18. Green M, Loewenstein PM (2006) Human adenoviruses: propagation, purification, quantification, and storage. Curr Protoc Microbiol, Chap. 14: unit 14C, p 11Google Scholar
  19. Grimm D, Kay MA, Kleinschmidt JA (2003) Helper virus-free, optically controllable, and two-plasmid-based production of adeno-associated virus vector of serotypes 1 to 6. Mol Ther 7:839–850PubMedCrossRefGoogle Scholar
  20. Halliday AM (1993) The visual evoked potential in healthy subjects. In: Halliday AM (ed) Evoked potentials in clinical testing, 2nd edn. Churchill Livingstone, Edinburgh, pp 57–113Google Scholar
  21. Holemans K, Van Bree R, Verhaeghe J, Meurrens K, Van Assche FA (1997) Maternal semistarvation and streptozotocin-diabetes in rats have different effects on the in vivo glucose uptake by peripheral tissues in their female adult offspring. J Nutr 127:1371–1376PubMedGoogle Scholar
  22. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736PubMedCrossRefGoogle Scholar
  23. Jehle T, Wingert K, Dimitriu C, Meschede W, Lasseck J, Bach M, Lagreze WA (2008) Quantification of ischemic damage in the rat retina: a comparative study using evoked potentials, electroretinography, and histology. Invest Ophthalmol Vis Sci 49:1056–1064PubMedCrossRefGoogle Scholar
  24. Johnson JE, Barde YA, Schwab M, Thoenen H (1986) Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J Neurosci 6:3031–3038PubMedGoogle Scholar
  25. Karunanayake EH, Hearse DJ, Mellows G (1975) The metabolic fate and elimination of streptozotocin. Biochem Soc Trans 3:410–414PubMedGoogle Scholar
  26. Kern TS, Barber AJ (2008) Retinal ganglion cells in diabetes. J Physiol 586:4401–4408PubMedCrossRefGoogle Scholar
  27. Kern TS, Miller CM, Du Y, Zheng L, Mohr S, Ball SL, Kim M, Jamison JA, Bingaman DP (2007) Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes 56:373–379PubMedCrossRefGoogle Scholar
  28. Kohzaki K, Vingrys AJ, Bui BV (2008) Early inner retinal dysfunction in streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci 49:3595–3604PubMedCrossRefGoogle Scholar
  29. Laquis S, Chaudhary P, Sharma SC (1998) The patterns of retinal ganglion cell death in hypertensive eyes. Brain Res 784:100–104PubMedCrossRefGoogle Scholar
  30. Lovasik JV (1983) An electrophysiological investigation of the macular photostress test. Invest Ophthalmol Vis Sci 24:437–441PubMedGoogle Scholar
  31. Lovasik JV, Kergoat H (1993) Electroretinographic results and ocular vascular perfusion in type 1 diabetes. Invest Ophthalmol Vis Sci 34:1731–1743PubMedGoogle Scholar
  32. Luu CD, Szental JA, Lee SY, Lavanya R, Wong TY (2010) Correlation between retinal oscillatory potentials and retinal vascular caliber in type 2 diabetes. Invest Ophthalmol Vis Sci 51:482–486PubMedCrossRefGoogle Scholar
  33. Machemer R, Sugita G, Tano Y (1979) Treatment of intraocular proliferations with intravitreal steroids. Trans Am Ophthalmol Soc 77:171–180PubMedGoogle Scholar
  34. Mansford KR, Opie L (1968) Comparison of metabolic abnormalities in diabetes mellitus induced by streptozotocin or by alloxan. Lancet 1:670–671PubMedCrossRefGoogle Scholar
  35. Maritim AC, Sanders RA, Watkins JB III (2003) Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 17:24–38PubMedCrossRefGoogle Scholar
  36. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC et al (2009) Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40–51PubMedCrossRefGoogle Scholar
  37. Moreo G, Mariani E, Pizzamiglio G, Colucci GB (1995) Visual evoked potentials in NIDDM: a longitudinal study. Diabetologia 38:573–576PubMedCrossRefGoogle Scholar
  38. Mosci C, Polizzi A, Grillo N, Capris P, Zingirian M (1986) Ottimizzazione del test del recupero maculare nello studio dei soggetti diabetici. Bol Ocul 65:347–356Google Scholar
  39. Ozkaya YG, Agar A, Hacioglu G, Yargicoglu P (2007) Exercise improves visual deficits tested by visual evoked potentials in streptozotocin-induced diabetic rats. Tohoku J Exp Med 213:313–321PubMedCrossRefGoogle Scholar
  40. Pan CH, Chen SS (1992) Pattern shift visual evoked potentials in diabetes mellitus. Gaoxiong Yi Xue Ke Xue Za Zhi 8:374–383PubMedGoogle Scholar
  41. Papakostopoulos D, Hart JC, Corrall RJ, Harney B (1996) The scotopic electroretinogram to blue flashes and pattern reversal visual evoked potentials in insulin dependent diabetes. Int J Psychophysiol 21:33–43PubMedCrossRefGoogle Scholar
  42. Parisi V (2001) Electrophysiological evaluation of the macular cone adaptation: VEP after photostress. A review. Doc Ophthalmol 102:251–262PubMedCrossRefGoogle Scholar
  43. Park K, Ryu SB, Park YI, Ahn K, Lee SN, Nam JH (2001) Diabetes mellitus induces vaginal tissue fibrosis by TGF-beta 1 expression in the rat model. J Sex Marital Ther 27:577–587PubMedCrossRefGoogle Scholar
  44. Parrilla-Reverter G, Agudo M, Sobrado-Calvo P, Salinas-Navarro M, Villegas-Pe′rez MP, Vidal-Sanz M (2009) Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury: a quantitative in vivo study. Exp Eye Res 89:32–41PubMedCrossRefGoogle Scholar
  45. Phipps JA, Yee P, Fletcher EL, Vingrys AJ (2006) Rod photoreceptor dysfunction in diabetes: activation, deactivation, and dark adaptation. Invest Ophthalmol Vis Sci 47:3187–3194PubMedCrossRefGoogle Scholar
  46. Puvanendran K, Devathasan G, Wong PK (1983) Visual evoked responses in diabetes. J Neurol Neurosurg Psychiatry 46:643–647PubMedCrossRefGoogle Scholar
  47. Raman PG, Sodani A, George B (1997) A study of visual evoked potential changes in diabetes mellitus. Int J Diab Dev Ctries 17:69–73Google Scholar
  48. Rancz EA, Franks KM, Schwarz MK, Pichler B, Schaefer AT, Margrie TW (2011) Transfection via whole-cell recording in vivo: bridging single-cell physiology, genetics and connectomics. Nat Neurosci 14:527–532PubMedCrossRefGoogle Scholar
  49. Seki M, Tanaka T, Nawa H, Usui T, Fukuchi T, Ikeda K, Abe H, Takei N (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 53:2412–2419PubMedCrossRefGoogle Scholar
  50. Shevtsova Z, Malik JMI, Michel U, Bähr M, Kügler S (2004) Promoters and serotypes: targeting of adeno-associated virus vectors for gene transfer in the rat central nervous system in vitro and in vivo. Exp Physiol 90:53–59PubMedCrossRefGoogle Scholar
  51. Shpak AA, Gavrilova NA, Poliakova MA (2010) Brain-derived neurotrophic factor in diabetic retinopathy and asymptomatic edema of the optic nerve head. Vestn oftalmol 126:7–10PubMedGoogle Scholar
  52. UK Prospective Diabetes Study Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317:703–713CrossRefGoogle Scholar
  53. Usta MF, Bivalacqua TJ, Yang DY, Ramanitharan A, Sell DR, Viswanathan A, Monnier VM, Hellstrom WJ (2003) The protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats. J Urol 170:1437–14422PubMedCrossRefGoogle Scholar
  54. Vadala M, Anastasi M, Lodato G, Cillino S (2002) Electroretinographic oscillatory potentials in insulin-dependent diabetes patients: a long-term follow-up. Acta Ophthalmol Scand 80:305–309PubMedCrossRefGoogle Scholar
  55. Vavra JJ, Deboer C, Dietz A, Hanka LJ, Sokolski WT (1959) Streptozotocin, a new antibacterial antibiotic. Antibiot Annu 7:230–235PubMedGoogle Scholar
  56. Weymouth AE, Vingrys AJ (2008) Rodent electroretinography: methods for extraction and interpretation of rod and cone responses. Prog Retin Eye Res 27:1–44PubMedCrossRefGoogle Scholar
  57. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053PubMedCrossRefGoogle Scholar
  58. Wu G, Weiter JJ, Santos S, Ginsburg L, Villalobos R (1990) The macular photostress test in diabetic retinopathy and age-related macular degeneration. Arch Ophthalmol 108:1556–1558PubMedCrossRefGoogle Scholar
  59. Yonemura D, Aoki T, Tsuzuki K (1962) Electroretinogram in diabetic retinopathy. Arch Ophthalmol 68:19–24PubMedCrossRefGoogle Scholar
  60. Zhao J, Pang S, Che G (2009) Specificity and sensitivity of visual evoked potentials P100 latency to different events exercise. Health 1:47–50CrossRefGoogle Scholar
  61. Zingirian M, Polizzi A, Grillo N (1985) The macular recovery test after photostress in normal and diabetic subjects. Acta Diabetol Lat 22:169–172PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yan Gong
    • 1
  • Zhan-Ping Chang
    • 2
  • Ruo-Tong Ren
    • 3
  • Shi-hui Wei
    • 1
  • Huan-Fen Zhou
    • 4
  • Xiao-fei Chen
    • 1
  • Bao-ke Hou
    • 1
  • Xin Jin
    • 1
  • Mao-nian Zhang
    • 1
  1. 1.Department of OphthalmologyChinese PLA General HospitalBeijingChina
  2. 2.Department of PathologyAerospace 731 HospitalBeijingChina
  3. 3.Institute of BiophysicsChinese Academy of SciencesBeijingChina
  4. 4.Department of OphthalmologyThe First Affiliated Hospital of General Hospital of PLABeijingChina

Personalised recommendations