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Henri O Leinonen, Tivadar Orban, Zhiqian Dong, Krzysztof Palczewski; Prevention of photoreceptor degeneration with FDA-accepted compounds. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1591.
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A combination therapy with drugs that act synergistically on G protein-coupled receptors has been shown to prevent rod photoreceptor cell death in mouse models of retinal degeneration. However, the extent of the protective effect for cone photoreceptors is unknown. We therefore examined whether the same combination therapy can preserve cone cells in a bright light-induced retinopathy model.
Abca4-/-/Rdh8-/- (DKO) mice were used. Retinal degeneration was instigated by bright light exposure (BLE, 25 klux for 0.5 h). Metoprolol, bromocriptine and tamsulosin (MBT) triple-treatment (10, 1 and 0.5 mg/kg bw; respectively) or vehicle was administered via intraperitoneal injection 0.5 h, 2 h or 4 h prior to BLE. We also tested the effect of additional dopaminergic drugs as monotherapy. Optical coherence tomography and electroretinography were performed 7 days after BLE. At 8 d post BLE, mice were sacrificed, and their retinas were processed for immunohistochemistry. Retinas were stained for S- and M-opsins and imaged using a fluorescence microscope. The elimination rate of MBT from the mouse circulation and eyes was also determined. Mice were sacrificed at different time points after drug administration and their collected serum and eyes were used for mass spectrometry analysis.
MBT prevented rod (P<0.001) and cone (P<0.01) cell degeneration in DKO mice when given 0.5 h prior to BLE. Cone cells also were protected when drugs were given 2 h prior to BLE (P<0.05) but rod cells were intermediately damaged (P<0.001). If the drugs were given 4 h prior to BLE, no rod or cone cell protection was observed in any mice. The D2-like dopamine receptor agonist pramipexole was protective as monotherapy at low doses (0.01 and 0.1 mg/kg bw, P<0.05 and P<0.001 respectively), whereas its low-affinity R(+) enantiomer dexpramipexole had no therapeutic effect. In pharmacokinetic experiments, M, B, and T were undetectable in serum samples within a few hours following their administration.
MBT treatment protects both rods and cones in a BLE-induced mouse model of retinal degeneration. However, the therapeutic effect decays rapidly after intraperitoneal administration, which coincides with the rate of drug elimination from the circulation. More sustained drug delivery will be needed for preclinical testing in chronic disease models.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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