Abstract
Purpose :
Retinitis pigmentosa (RP) is a blinding disease caused by multiple mutations in dozens of genes; therefore, a gene agnostic treatment approach to prevent photoreceptor (PR) degeneration is ideal. We previously demonstrated that pharmacological activation of pyruvate kinase M2 (PKM2) alters central glucose metabolism and is neuroprotective for PRs in a model of acute outer retinal nutrient stress. Additionally, microglia can adopt an inflammatory phenotype, which has been shown to contribute to PR degeneration in RP, and PKM2 has been shown to suppress this inflammatory phenotype in other systems. This study assesses the pharmacologic activation of PKM2 as a novel therapeutic avenue in the rd10 mouse model of RP.
Methods :
We employed oral (PO) and intraperitoneal (IP) injections of a known PKM2 activator, ML-265, and a novel PKM2 activator, MCTI-566, in rd10 and wild-type mice from postnatal day 14 (P14) to 49 (P49). At various time-points, the overall retinal PK activity was measured using an enzyme coupled continuous assay that measures the depletion of NADH at 340 nm. In vivo retinal structure and function analyses quantitatively examined the effect of PKM2 activation on retinal degeneration in rd10 mice. Histology and flow cytometry characterized retinal morphology and microglia recruitment and polarization.
Results :
PK activity is depressed by over 40% (p < 0.001) in rd10 retinas at P14 compared to age-matched wild type animals, prior to any observed PR degeneration. PO administration of ML-265 significantly increased PK activity in rd10 retinas by over 1.5-fold (p < 0.01), which was similarly demonstrated with IP MCTI-566. Flow cytometry demonstrated a significant increase in rd10 retinal microglial numbers with a shift toward the pro-inflammatory M1 phenotype.
Conclusions :
We previously showed that enhancing retinal PK activity using a small molecule activator of PKM2 is neuroprotective in a model of acute nutrient deprivation. Our new data suggest that decreased PKM2 activity and altered microglial polarization may contribute to PR degeneration in the rd10 mouse model of RP. Therefore, the use of small molecule PKM2 activators as a non-gene-specific therapy may prevent these metabolic and immunologic perturbations in RP.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.