Search

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., Eye disease: switching signals for repairing injured optic nerves Regulating molecular signaling pathways that control the degradation of cellular components—a process known as autophagy—could offer a new approach to treating optic nerve damage after traumatic injuries. There is currently no established treatment option for traumatic optic nerve injury. Rong-Kung Tsai and colleagues at Tzu Chi University in Hualien, Taiwan, explored the role of a protein complex called mTORC2 in autophagy during the repair of optic nerves in rats. They investigated mTORC2 activation by small RNA molecules that also activate autophagy, and by drugs that activate autophagy but inhibit mTORC2. The results indicate that autophagy associated with activation of mTORC2 protects damaged retinal neurons and promotes visual recovery. In addition to treating optic nerve injuries, drugs activating mTORC2 and autophagy might help treat nerve-related diseases of the eye, including glaucoma.

Reproducible skills are essential for successful induction of a rat model of anterior ischemic optic neuropathy (rAION). We established an in vivo validation index by measuring the natural course of optic nerve head (ONH) width and retinal nerve fiber layer (RNFL) thickness in the rAION model using optical coherence tomography (OCT). The rAION model was induced by photodynamic operations. We measured the ONH width, RNFL, Inner Plexiform layer (IPL) and Ganglion cell complex (GCC) thickness in the acute stage (3 days), subacute stage (day-7 to day-14) and later stage (day-14 to day-28) post-infarct by OCT. Retinal layers were measured by hematoxylin and eosin stain (HE) to confirm the OCT findings. The RGCs survival rate was determined by retrograde Fluoro-gold labeling, and the visual function was assessed with flash visual-evoked potentials (FVEPs) 4 weeks post-infarct. We observed significant thinning in GCC, IPL, and RNFL at day-14 and day-28 but only RNFL showed significant thinning between day-14 and day-28. The ONH showed significant swelling in the acute stage which correlated at a greater extent with RNFL than GCC and IPL. Further RNFL correlated at a greater extent at with GCC than IPL. HE-stained retina cross sections also showed IPL and RNFL thinning, which further confirmed our OCT findings. The RGC density and P1-N2 amplitude were significantly reduced in rAION. Our data suggest that Swelling, reduction of swelling, and atrophy of RNFL in acute, sub-acute, and later stage, respectively and ONH swelling in the acute stage are essential events for confirming the successful induction of rAION.

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.

Purpose This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1β, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPβ in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.

Retinal ischemic injuries play an important role in the pathogenesis of several eye disorders. Inflammation and oxidative stress are key players in ischemic injuries. Following retinal ischemia, vascular endothelial cells and leukocytes express several inflammatory adhesion receptors, such as selectins and cell adhesion molecules. P-selectin stimulates leukocyte recruitment to platelet aggregates and has an important role in vascular homeostasis and inflammatory leukocyte extravasation. Soluble P-selectin can be neuroprotective through competitive binding to the receptors of endogenous P-selectin molecules. Here, we demonstrate the neuroprotective effect of a recombinant P-selectin immunoglobin G (P-sel-IgG) chimeric fusion protein in a rat anterior ischemic optic neuropathy (rAION) model. rAION was induced by photodynamic therapy. P-sel-IgG treatment reduced optic nerve edema and stabilized the blood–optic nerve barrier (BONB) in the acute phase of rAION. Further, P-sel-IgG increased the retinal ganglion cell (RGC) survival rate, reduced RGC apoptosis, preserved visual function, maintained retinal nerve fiber layer thickness, and reduced macrophage infiltration in optic nerve tissue in the chronic phase (day 28). Increased NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1(HO-1) expression levels, along with increased transcription factor Nrf2, suggesting an antioxidant role of P-sel-IgG via the Nrf2 signaling pathway. In conclusion, this study is the first to demonstrate that P-sel-IgG treatment promotes RGC survival by stabilizing the BONB and activating the Nrf2 signaling pathway in a rAION model.

Purpose To investigate the effect of oroxylin A on the survival of retinal ganglion cells (RGC) and the activation of microglial cells in a rat optic nerve (ON) crush model. Methods Oroxylin A (15mg/Kg in 0.2ml phosphate-buffered saline) or phosphate-buffered saline (PBS control) was immediately administered after ON crush once by subcutaneous injection. Rats were euthanized at 2 weeks after the crush injury. The density of RGC was counted by retrograde labeling with FluoroGold and immunostaining of retina flat mounts for Brn3a. Electrophysiological visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the retinas, and immunohistochemistry of GFAP in the retinas and ED1 in the ON were evaluated. Results Two weeks after the insult, the oroxylin A-treated group had significantly higher FG labeled cells and Brn3a+ cells suggesting preserved RGC density in the central and mid-peripheral retinas compared with those of the PBS-treated group. FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, oroxylin A-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, oroxylin A-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON-crushed, oroxylin A-treated group. Increased GFAP expression in the retina was reduced greatly in ON-crushed, oroxylin A-treated group. Furthermore, administration of oroxylin A significantly attenuated ON crush insult-induced iNOS and COX-2 expression in the retinas. Conclusions These results demonstrated that oroxylin A hasss neuroprotective effects on RGC survival with preserved visual function and a decrease in microglial infiltration in the ONs after ON crush injury.