Abstract
PURPOSE: A corneal alkali burn can cause irreversible damage to both the cornea and retina. This study aims to investigate the role of the gap junction subunit connexin 36 (Cx36) in mediating secondary cell death and its impact on the apoptosis of retinal ganglion cells (RGCs) following ocular alkali burns, contributing to irreversible vision loss. METHODS: Corneal alkali burn models were established in C57BL/6J and Cx36 knockout (KO) mice by applying 1 M sodium hydroxide to the cornea. The gap junction blocker meclofenamic acid (MFA; 200 µM) was administered via intravitreal injection immediately after the corneal alkali burn. Immunohistochemistry was used to assess RGC survival, whereas patch-clamp recording evaluated the RGC function. RESULTS: In the mouse model, dysfunction and cell death in RGCs were observed within 6 hours following ocular alkali burns. Our results showed a time-dependent increase in RGC loss, peaking at 24 hours, with damage spreading from the peripheral to the central regions. The study revealed a significant reduction in light sensitivity and light-evoked excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) in ON and OFF transient alpha RGCs after 6 hours of corneal alkali burns. The Cx36 knockout mice exhibited significantly increased RGC survival. The data suggests that MFA has a neuroprotective effect, preventing secondary RGC damage. CONCLUSIONS: Our findings indicate that Cx36 gap junctions mediate secondary cell death of RGCs following corneal alkali injuries and may serve as a potential target for neuroprotective therapy. The gap junction antagonist MFA, a US Food and Drug Administration (FDA)-approved drug, could prevent this secondary cell death, highlighting its potential as a therapeutic intervention.