Biopolymer-Conjugated Human C-Peptide Provides Sustained Neuroprotection and Preserves Axonal Transport in a Mouse Model of NMDA-Induced Retinal Degeneration via Antioxidative Mechanisms

초록

Glutamate excitotoxicity is a key contributor to the pathogenesis of glaucoma, a leading cause of irreversible blindness worldwide; however, the molecular events driving progressive retinal ganglion cell (RGC) loss and axonal degeneration remain incompletely understood, and effective neuroprotective therapies are lacking. Here, we evaluated the preventive potential of K9-C-peptide, a biopolymer-conjugated human C-peptide, in a mouse model of N-methyl-D-aspartate (NMDA)-induced retinal neurodegeneration and optic nerve axonal transport impairment, and examined potential mechanisms underlying its protective effects. In NMDA-induced excitotoxic mouse retinas, intracellular Ca2+ elevation mediated NMDA-induced oxidative stress, including both intracellular and mitochondrial reactive oxygen species (ROS) generation and lipid peroxidation. NMDA exposure induced activation of M & uuml;ller glia and microglia and upregulation of inflammatory cytokines, ultimately leading to RGC death; these effects were attenuated by prolonged intraocular delivery of ROS scavengers. K9-C-peptide significantly reduced NMDA-induced retinal degeneration, including RGC loss and retinal thinning, and preserved optic nerve axonal transport function in both whole-mount retinas and optic nerve longitudinal sections. These protective effects were associated with suppression of NMDA-induced oxidative stress, mitochondrial dysfunction, and inflammation and reactive gliosis, without altering intracellular Ca2+ levels. Notably, sustained intraocular delivery of human C-peptide conferred robust neuroprotection for at least 3 weeks against NMDA-induced retinal degeneration and optic nerve axonal transport impairment. These findings suggest that K9-C-peptide acts as a long-acting neuroprotective agent that mitigates oxidative stress-driven retinal damage and axonal dysfunction, highlighting its translational potential as a C-peptide-based neuroprotective strategy for retinal glutamate excitotoxicity.

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