Purchase this article with an account.
G.S. Okoye, J. Zimmer, J. Sung, P. Gehlbach, T. Deering, H. Nambu, S. Hackett, N. Esumi, D.J. Zack, P.A. Campochiaro; Increased Expression of Brain-Derived Neurotrophic Factor Preserves Retinal Function and Slows Cell Death from Rhodopsin Mutation or Oxidative Damage . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3146.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Studies examining the effects of intravitreous injections of BDNF have suggested that it has little survival-promoting activity for photoreceptors in models of inherited retinal degenerations. The purpose of this study was to investigate the effects of sustained expression of BDNF in models of retinal degeneration. Methods: Five independent lines of reverse tetracycline transactivator (rtTA)/IRBP-tetracycline response element (TRE)/BDNF double transgenic mice were generated. Expression of BDNF was evaluated by RT-PCR and immunohistochemistry. The effect of sustained expression of BDNF was examined in two models of retinal degeneration, mice exposed to hyperoxia and transgenic mice that express truncated Q344ter rhodopsin. The posterior retina outer nuclear layer (ONL) thickness were deteremined, and compared between transgenics that expressed BDNF and those that did not express BDNF. Retinal function was evaluated by ERGs. Results: One line of double transgenic mice showed high expression of BDNF mRNA and BDNF protein in the retina in the presence of doxycycline (DOX), and minimal expression in the absence of DOX, and this line was used for all experiments. Double transgenics exposed to hyperoxia for 2 weeks showed marked degeneration of photoreceptors throughout the posterior portion of the retina that was prevented by doxycycline-induced expression of BDNF (p < 0.0001). Double transgenics mated with Q344ter mice to generate triple hemizygous transgenics, also showed significantly thicker ONL at P16 and P21 when treated with DOX compared to untreated triple transgenics (p < 0.0001). Doxycycline-treated triple transgenics had significantly greater a- and b-wave ERG amplitudes compared to non doxycycline-treated triple transgenics (p < 0.0001) demonstrating BDNF-induced rescue of retinal function as well as structure. There was no decline in ERG amplitudes in double transgenics that had doxycycline-induced expression of BDNF in the retina for 2 weeks compared to those not treated with doxycycline, suggesting non-deleterious effect of continuous BDNF expression on retina function. Conclusions: These data suggest that continuous expression of BDNF, unlike intravitreous injections, results in morphologic and functional benefit in animal models of retinal degeneration. Double transgenic mice with inducible expression of survival factors provide valuable tools for selection of survival factor candidates for gene therapy.
This PDF is available to Subscribers Only