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M. Agudo, P. Sobrado, C. Pérez-Marín, U. Lönngren, M. Salinas, I. Cánovas, J. Miralles-Imperial, F. Hallböök, M. Vidal-Sanz; BDNF-Induced Gene Expression Changes in Axotomized Adult Rat Retinas. Invest. Ophthalmol. Vis. Sci. 2007;48(13):645.
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To understand the molecular mechanisms underlying the protection afforded by brain derived neurotrophic factor (BDNF) against axotomy-induced RGC death
In adult Sprague-Dawley rats, the left optic nerve was intraorbitally transected (IONT) and 5 µg of BDNF or vehicle solution (VEH) were injected intravitreally immediately after. By means of DNA microarrays we have analyzed and compared the transcriptome of adult retinas suffering IONT+BDNF or IONT+VEH. We have compared these data with our previous analysis of retinal transcriptome regulation after IONT or intraorbital nerve crush (IONC). At 12h, 24h, 48h, 3d or 7d after IONT (n=12 per time point and treatment), retinas were quickly extracted and RNA processed for microarray hybridization (Affymetrix: rae 230.2). Biological replicas of the arrays were done (n=3) and data collected. Data were normalized and statistically analysed using the Bioconductor software (Limma and maSigPro packages). Regulated genes were functionally annotated and grouped based on their molecular function and on the biological process they participate in (DAVID).
After IONT, IONT+VEH and IONC genes traditionally associated with RGC well-being, as Thy1 and Nfm are greatly down-regulated starting at 12h post-lesion (pl). Interestingly, BDNF injection maintains these genes at their normal level up to 3dpl, when their RNA starts to drop. With respect to death-associated genes, our data indicate that even though BDNF neuroprotects RGCs at anatomical level up to 5 dpl, caspase 3 is highly up-regulated by 24hpl. However, this increase in caspase 3 RNA differs from IONT where it is up-regulated earlier, at 12hpl
Expression of RGC associated genes, as Thy1 and Nfm is kept at normal levels for a longer period after IONT+ BDNF than after IONT and IONC. This agrees with previous reports demonstrating that a single intraocular injection of BDNF may prevent RGC loss, as shown with anatomical techniques. The difference in the time course expression of the pro-apoptotic molecule caspase 3 observed in these groups, may account for part of the neuroprotection afforded by BDNF
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