Sustained delivery of neurotrophic growth factors from biodegradable microspheres after acute elevation of intraocular pressure in rats

Abstract

Abstract: : Purpose: To functionally characterize the status of the rat retina and optic nerve after acute elevation of intraocular pressure (IOP) and to determine if release of neurotrophic growth factors from biodegradable microspheres can decrease functional and morphological damage of the retina and/or optic nerve in acute ischemic rat eyes. Methods: Retinal ischemia was induced in rats by increasing the IOP (110 mmHg/60 minutes). Microspheres for slow release of neurotrophic factors were made using a spontaneous emulsification technique forming poly(lactic–co–glycolic acid)(PLGA) spheres. Microspheres (BDNF, GDNF, CNTF or blank/control) were injected into the vitreous 1 day after elevation of IOP. A fifth group of rats received elevated IOP, but no microspheres. Direct and consensual pupil light reflexes (PLR) were recorded from unoperated eyes preoperatively and at days 10, 20, 30, 40, 50 and 60 postoperatively. Electroretinograms (flash and flicker ERG, oscillatory potentials) were recorded from the operated and control eyes (preop. and 60 days postop.). Results: Detailed analysis of PLR amplitudes presented as the PLR_ratio (ratio=consensual/direct PLR) showed that rats receiving BDNF or GDNF microspheres had significantly better PLR amplitudes (One–way ANOVA, Bonferroni’s Multiple Comparison Test) compared to the groups which received blank microspheres 24h postoperatively or no microspheres. The average values were: PLR_ratio(BDNF) = 54.5+1.5% (p<0.001), PLR_ratio(GDNF) = 48+3% (p<0.05), PLR_ratio(CNTF) = 44.3+1.6% (p>0.05), PLR_ratio(blank) = 39.1.5+1.8%, PLR_{ratio(no microspheres)} = 36.4+4.4%. ERG data analysis revealed no statistically significant difference between all groups. Histological analysis revealed severe damage in all retinas that were subjected to the elevated IOP. However, slightly less damage was observed in those eyes that received neurotrophic growth factor releasing microspheres when compared to the controls (blank or no microspheres). Conclusions: The results suggest sustained release of BDNF and GDNF from microspheres may protect the inner retina and optic nerve (PLR function), while no such protection was seen with the outer retina (ERG). Microspheres engineered to release neurotrophic factors may be a promising strategy for drug delivery for the treatment of optic nerve ischemic disease.

Keywords: intraocular pressure • growth factors/growth factor receptors • ischemia