L-DOPA treatment promotes sustained neurovascular and synaptic homeostasis in the diabetic retina

Purpose: Previous work has shown a sustained protective effect of levodopa (L-DOPA) on retinal function in early-stage diabetic retinopathy in humans. Here, we quantify neurovascular function, investigate the longevity of L-DOPA treatment for sustained retinal protection, and assess gene expression changes to identify underlying biology in a diabetic mouse model. Methods: After confirming retinal functional deficits in streptozotocin (STZ)-induced diabetic mice using electroretinogram (ERG) and optomotor response (OMR), control and diabetic mice were treated with: 1) L-DOPA/carbidopa for four weeks (continuous), 2) two weeks of L-DOPA/two weeks of washout, or 3) vehicle for four weeks. During the final two weeks of treatment, ERG and OMR testing was repeated and the vasodilative response to photic flicker stimulus was measured to evaluate neurovascular coupling. Following retinal extraction, bulk RNASeq analyses of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and gene ontology (GO) were used to relate neurovascular functional protection with retinal gene expression. Results: L-DOPA treatment improved ERG oscillatory potential timing and OMR responses in diabetic mice, with improvements maintained during the washout period. Flicker-induced venule vasodilative response also showed sustained improvement in the diabetic L-DOPA washout group. DEGs in the diabetic retina were similar across L-DOPA treatment groups. WGCNA revealed that L-DOPA treated diabetic mice had specific gene modules associated with synapse function and cytoskeletal components that correlated with L-DOPA-induced retinal function protection. Conclusions: L-DOPA treatment restored and sustained protection of retinal neurovascular function in early-stage diabetic retinopathy in mice. These improvements in function were associated with transcriptional changes related to retinal synapse activity and cytoskeletal integrity.