Abstract
Purpose :
The effect of KCNQ-targeting drugs on the visual light response (VLR) is unknown. Previous studies have demonstrated the expression of these channels in the retina and retinal pigment epithelium (RPE). Patients note persistent visual disturbances while using the KCNQ-activating anti-epileptic drug Retigabine. Given that KCNQ subunits are also expressed in the retina, we sought to identify how KCNQ modulators alter rodent retinal function.
Methods :
VLR was assessed with ex-vivo or full field electroretinograms (exERG, ffERG). For exERGs, retinae were removed from freshly enucleated mice eyes and stimulated using OcuScience’s ex-vivo ERG (custom protocol). Baselines were recorded in Ames medium. Retinae were incubated in 10 µM Zinc Pyrithione (ZP), 10 µM RL-648_81 (RL), 10 µM XE-991 (XE), 50 µM L-AP-4 (positive), 0.5% DMSO or 0.1% PBS treated Ames for 20 minutes. Another exERG was then taken, and a final recording after a 20-minute Ames wash. ffERGs were performed on the Espion-E3 system using the ISCEV protocol to assess a and b-waves and a custom c-wave protocol. Recordings consisted of a baseline, ffERG 15 minutes after treatment, and a follow-up after 3 days. Drugs were injected intravitreally for final vitreal concentrations given above. Two-tailed Student’s t-test was used for data analysis.
Results :
ExERGs revealed b-wave amplitude reductions in ZP treated retina (89 ± 22 µV) compared to baseline, (247 ± 38 µV, p = 0.01), which persisted post-wash. b-wave implicit time (IT) increased in ZP treated groups (116 ± 10 ms) relative to baseline (78 ± 6 ms, p = 0.009). Amplitude decrease was not observed with concurrent XE and ZP treatment, but IT was still delayed.
For ffERGs, b-wave and c-wave amplitude of ZP treated eyes decreased (233 ± 24, 161 ± 61 µV) compared to baseline (408 ± 31, 523 ± 37 µV, p = 0.001, 0.0008). b-wave IT decreased after ZP treatment (66 ± 13 ms) relative to baseline (32 ± 1 ms, p = 0.03). Interestingly, RL treatment increased a-wave amplitude (178 ± 17 µV) above baseline (113 ± 19 µV, p = 0.04). All mice had normal follow-up ffERGs.
Conclusions :
Our results show that KCNQ modulation may alter retinal function. However, differences between the RL and ZP responses suggest non-uniform expression of functional KCNQ subunits in the retina. Exploration of ocular KCNQ distribution and modulation in specific retinal circuits will further elucidate the role of KCNQ channels in VLR.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.