L-DOPA Promotes Post-Treatment Neurovascular and Synaptic Homeostasis in Early Diabetic Retinopathy

Purpose: Although previous work has shown a post-treatment protective effect of levodopa (L-DOPA) on retinal function in early-stage diabetic retinopathy (DR) in humans, its underlying biology is unknown. This study investigated L-DOPA's post-treatment functional protection with transcriptional changes in the diabetic murine retina. Methods: Assessing retinal and visual function with electroretinography (ERG) and optomotor response (OMR), functional deficits were confirmed in streptozotocin (STZ)-induced diabetic mice. Control and diabetic mice were then treated with continuous L-DOPA/carbidopa (four weeks), L-DOPA/carbidopa (two weeks) followed by washout (two weeks), or vehicle (four weeks). Functional assessments were repeated during the final two weeks, alongside assessment of flicker-evoked retinal vasodilation. After bulk RNA sequencing of retinal tissue, differential gene expression analysis alongside weighted gene co-expression network analysis were performed to determine disease- and treatment-sensitive changes in retinal gene co-expression that correlated with functional protection. Results: After L-DOPA treatment in diabetic mice, ERG oscillatory potential timing and OMR performance were protected for at least two weeks past treatment end. Flicker-induced venule vasodilation also maintained post-treatment improvement, with protective trends in arteriole vasodilation. Differentially expressed genes were comparable between diabetic mice experiencing L-DOPA washout versus continued L-DOPA treatment. Gene co-expression network analysis identified distinct modules across L-DOPA-treated diabetic mice associated with synaptic function and cytoskeletal organization that correlated with functional protection. Conclusions: These findings demonstrate that L-DOPA restores retinal neurovascular function with post-treatment effects in early DR and links this protection to transcriptional programs supporting synapse activity and structural integrity.