Inhibiting The uPA/uPAR Pathway Affords Photoreceptor Resilience and Preserves Retinal Function in a Mouse Model of Retinitis Pigmentosa

Purpose: Retinitis pigmentosa (RP) is characterized by primary rod degeneration followed by secondary cone death. The urokinase-type plasminogen activator (uPA) and its cognate receptor (uPAR) have been recently suggested to regulate pro-inflammatory events in RP possibly through the interaction of uPAR with its lateral partners, including formyl peptide receptors (FPRs). This study explored whether the inhibition of the crosstalk between uPAR and FPR1 may counteract photoreceptor degeneration in the rd10 mouse model of RP. Methods: The newly synthetized FPR1 antagonist N-19004 was subcutaneously administered to rd10 mice from post-natal day (PD) 10 to PD 30. The efficacy of N-19004 on retinal function and morphology was evaluated by electroretinogram (ERG) and optical coherence tomography (OCT), respectively. Immunofluorescence and Western blotting for key markers of photoreceptors, immune cells, gliosis, inflammation, oxidative stress, and downstream effectors of FPRs were also performed. Results: N-19004 attenuated retinal dysfunction and mitigated both rod and cone degeneration. N-19004 administration also reduced activation of immune cells, gliosis, inflammation, oxidative stress, and apoptosis. The activation of Akt and ERK1/2 pathways was likely to be involved in the effects of N-19004. Conclusions: N-19004 increases photoreceptor resilience and preserves retinal function in rd10 mice. These effects are likely to be due to an N-19004-mediated reduction of neuroinflammation and oxidative stress, suggesting a novel therapeutic strategy for the treatment of RP.