Irreversible vision loss due to retinal ganglion cell (RGC) apoptosis often results from excitotoxicity caused by overactivation of N-methyl-D-aspartate (NMDA) receptors.
This process induces excessive calcium (Ca²⁺) influx, affecting proteins such as Calpain-1, Cabin-1, and Calcineurin and triggering apoptotic pathways involving BAX, Caspase-3, and BCL.
This study evaluated the neuroprotective effects of Philanthotoxin-343 (PhTX-343) against NMDA-induced retinal and optic nerve damage in rats.
Rats were divided into three groups: PBS (control), NMDA, and PhTX-343 pre-treatment (administered 24 hours before NMDA).
Visual behavior was assessed seven days post-treatment, followed by histological and molecular analyses of retinal and optic nerve tissues.
The NMDA group showed significant retinal thinning, loss of cell nuclei in the ganglion cell layer (GCL), reduced Brn3A (RGC marker) expression, and disrupted protein levels—elevated Calpain, Calcineurin, BAX, and Caspase-3, with decreased Cabin-1 and BCL—compared to the PBS group (p < 0.05).
Behaviorally, NMDA exposure resulted in hyperactivity, reduced immobility, and impaired novel object recognition (p < 0.05).
PhTX-343 pre-treatment preserved retinal and optic nerve morphology, resembling the PBS group.
Brn3A-positive RGCs were significantly higher than in the NMDA group (p < 0.05) and comparable to controls (p > 0.05). Protein levels in the PhTX-343 group were normalized, with lower Calpain, Calcineurin, BAX, and Caspase-3, and higher Cabin-1 and BCL compared to the NMDA group (p < 0.05).
Visual performance in PhTX-343-treated rats improved significantly, with behavior akin to the PBS group (p > 0.05).
In conclusion, PhTX-343 protects against NMDA-induced excitotoxicity by modulating calcium-related and apoptotic proteins, preserving retinal and optic nerve integrity, and restoring visual function in rats.