Naringenin and quercetin alter mouse rod phototransduction kinetics in a manner consistent with phosphodiesterase-6 inhibition

Background: The flavonoids naringenin and quercetin are promising therapeutic agents for a wide variety of diseases, including inherited retinal degenerations (IRDs), thanks to their antioxidant, anti-inflammatory, and other properties. Among these are their inhibition of some phosphodiesterase (PDE) isoforms. However, it is unknown how they affect the photoreceptor-specific PDE6, which is critical for phototransduction. This interaction is key for understanding their therapeutic potential in IRDs and the risk of visual side effects more broadly. We aimed to determine if they inhibit PDE6 in living mouse retinae at pharmacologically relevant concentrations. Methods: We used ex vivo electroretinography to record pharmacologically isolated rod a-waves from mouse retinae at 37 °C. One retina received naringenin or quercetin, while the other received the vehicle. We analysed flash response parameters: light sensitivity, time-to-peak, amplification constant (derived by fitting responses with a biophysical model), and saturating amplitude. Results: Both flavonoids rapidly decreased amplification, in line with inhibition of light-activated PDE6 with a of 7.1 µM for naringenin and 15.1 µM for quercetin. Naringenin increased saturating amplitude, consistent with inhibiting dark-state PDE6. Quercetin induced a secondary slowing of phototransduction cascade termination kinetics independent of its effect on amplification, suggesting inhibition of a cascade shutdown protein. Conclusions: These findings are key to evaluating the visual safety of high-dose flavonoid therapies. They also raise the possibility that direct effects on phototransduction could play a role in their neuroprotection in IRDs.