FPR1 Antagonist N-19004 Reduces Blood-Retinal Barrier Breakdown and Improves Retinal Function in Diabetic Rats

Diabetic retinopathy (DR) is a leading cause of blindness, characterized by early neurovascular damage driven by hyperglycemia-induced inflammation. Current treatments often target late-stage vascular complications, leaving a significant gap in addressing the initial neurovascular alterations. The urokinase-type plasminogen activator receptor (uPAR) system has been implicated in pro-inflammatory events in DR, potentially through its interaction with formyl peptide receptors (FPRs). Specifically, the uPAR/FPR1 crosstalk represents a novel target for mitigating early DR pathology by modulating inflammation.

Researchers investigated the FPR1 antagonist N-19004 in a rat model of streptozotocin-induced diabetes to assess its impact on early neurovascular changes. N-19004 was administered subcutaneously for 7 days starting 1 month after diabetes onset. The study evaluated inflammation, reactive gliosis, blood-retinal barrier (BRB) integrity, and apoptosis using immunofluorescence, RT-qPCR, Western blot, and Evans blue perfusion. Retinal function was assessed via electroretinogram (ERG) to determine N-19004's efficacy.

Treatment with N-19004 significantly inhibited the activation of key inflammation-related transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3). This inhibition led to reduced expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). The attenuation of these inflammatory processes resulted in decreased glial activation, evidenced by lower glial fibrillary acidic protein (GFAP) expression and reduced Müller cell gliosis. The anti-inflammatory effects of N-19004 were directly linked to a substantial decrease in BRB breakdown. This was demonstrated by a reduction in vascular endothelial growth factor (VEGF), increased levels of tight junction components, and diminished vessel leakage. The amelioration of BRB integrity was further associated with reduced activation of caspase 3, a marker of apoptosis.

N-19004 treatment led to partial preservation of scotopic ERG a- and b-wave amplitudes, indicating improved retinal viability and function in the diabetic rats.