Abstract
Traumatic optic neuropathy is an injury to the optic nerve that leads to vision loss. Autophagy is vital for cell survival and cell death in central nervous system injury, but the role of autophagy in traumatic optic nerve injury remains uncertain. Optic nerve crush is a robust model of traumatic optic nerve injury. p62 siRNA and rapamycin are autophagy inducers and have different neuroprotective effects in the central nervous system. In this study, p62 and rapamycin induced autophagy, but only p62 siRNA treatment provided a favorable protective effect in visual function and retinal ganglion cell (RGC) survival. Moreover, the number of macrophages at the optic nerve lesion site was lower in the p62-siRNA-treated group than in the other groups. p62 siRNA induced more M2 macrophage polarization than rapamycin did. Rapamycin inhibited both mTORC1 and mTORC2 activation, whereas p62 siRNA inhibited only mTORC1 activation and maintained mTORC2 and Akt activation. Inhibition of mTORC2-induced Akt activation resulted in blood–optic nerve barrier disruption. Combined treatment with rapamycin and the mTORC2 activator SC79 improved RGC survival. Overall, our findings suggest that mTORC2 activation after autophagy induction is necessary for the neuroprotection of RGCs in traumatic optic nerve injury and may lead to new clinical applications.
Highlights
Traumatic optic neuropathy (TON) is damage to the optic nerve caused directly or indirectly by assault, head trauma, disasters, or road accidents
The present study investigated the role of autophagy by observing rapamycin-mediated and p62-mediated mTOR activation in a rat model of optic nerve crush (ONC)
The amplitudes of the P1-N2 waves showed no significant difference between the rapamycin-treated group and scrambled-siRNAtreated group (Fig. 2b)
Summary
Traumatic optic neuropathy (TON) is damage to the optic nerve caused directly or indirectly by assault, head trauma, disasters, or road accidents. TON results in optic nerve edema, disrupting the pial vessels and limiting the vascular supply. These events trigger an inflammatory response at the injury site, causing secondary damage to the optic nerve, which leads to axon degeneration and retinal ganglion cell (RGC) death[1,2]. Within hours after optic nerve injury, there is a rapid increase in autophagic vesicles at the optic nerve lesion, which spread back to the RGC somata where LC3 levels are increased as early as 24 h after a lesion[11]. The transcriptional levels of autophagy-related genes such as Atg[5] and Atg[7] in RGC somata are increased between 3 and 10 days after a lesion[13]. A substantial increase in p62 in the optic nerve could be caused by insufficient autophagic flux or parallel upregulation of p6214,15
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