Abstract
Purpose: :
We have recently demonstrated that amyloid-ß (Aß) is associated with glaucoma, and that its targeting significantly reduces retinal ganglion cell (RGC) apoptosis in experimental glaucoma. In this study, we have investigated long-term effects of combination verses single agent therapy targeting Aß in glaucoma treatment.
Methods: :
Using a rat model of chronic ocular hypertension (OHT), we intravitreally administered single, dual and triple combinations of three different agents targeting Aß pathway at the time of surgical IOP elevation: monoclonal anti-Aß antibody (Aßab (0.5mg/ml, n=5), Congo red (CR, 1.46mg/ml, n=5), ß-secretase inhibitor (ßSI, 10µg/ml, n=5), and vehicle control (n=5). For combination therapy (Triple (Aßab+CR+ßSI), Dual1(Aßab+CR), Dual2 (Aßab+ßSI)) individual treatments were combined with the same doses as in the monotherapy. Animals were imaged for RGC apoptosis at 3, 8 and 16 weeks after IOP elevation using our novel DARC (Detection of Apoptosing Retinal Cells) imaging method and then sacrificed for histology.
Results: :
All combination therapies targeting different aspects of Aß pathway showed a reduction of RGC apoptosis at 3, 8 and 16 weeks compared to vehicle control although this was only significant at 3 weeks (p<0.05). Triple therapy was found to be the most effective combination regimen in prevention of RGC death, consistently reducing levels of RGC apoptosis by 84%, 66% and 75% at 3, 8 and 16 weeks compared to 74%, 58% and 51% with Aßab alone (which was the most effective monotherapy), although this effect was only statistically significant at 3 weeks (p<0.05). Dual therapies showed no statistical difference from Aßab alone or control at all the time points observed.
Conclusions: :
Combination treatments targeting different stages of amyloid-ß pathway appear more effective than single agent treatment in reducing RGC apoptosis in experimental glaucoma. However, this is only significant at 3 weeks after IOP elevation. We attribute the lack of a long-term effect to the fact that treatment was only given as a single application at the time of IOP elevation. We plan to shortly report on the effects of repeated applications of combination therapy.
Keywords: neuroprotection • apoptosis/cell death • pathology: experimental