Browsing by Subject "JNK"
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Item DIFFERENTIAL ACTIVATION OF P38 AND C-JUN N-TERMINAL KINASE IN THE VISUAL PATHWAY FOLLOWING OPTIC NERVE CRUSH(2013-04-12) Liu, YangPurpose: p38 and c-jun N-terminal kinase (JNK) are two major stress-activated signaling pathways. In this study, we compared the activation of p38 and JNK in the retina, optic nerve, and superior colliculus after optic nerve crush (ONC) in adult mice. Methods: ONC was performed unilaterally in adult mice. The damage to the retinal ganglion cell (RGC) layer and superior colliculus (SC) was determined by Nissl and black gold II staining. The activation of p38 and JNK in the retina, optic nerve, and superior colliculus was examined by immunofluorescence staining. Results: Starting from 4 weeks after ONC, there were very few RGCs remaining in the RGC layer and fewer neurons (P < 0.05) in the contralateral SC compared to the control group. The volume of the contralateral SC was smaller (P < 0.01) than that of the control group. Phosphorylated JNK (p-JNK) was observed mainly on the proximal side of the optic nerve crush site as early as 1 hour after ONC. The expression of phosphorylated c-JUN was detected in the RGC layer starting 24 hours after ONC. The activation of p38 started 3 days post-ONC and was observed on both sides of the crush site. An increase of phosphorylated p38 (p-p38) was detected in the inner nuclear layer of the retina from 3 through 28 days following ONC. Two weeks after ONC, both p-JNK and p-p38 increased in the contralateral SC; however, the p38 activation was also observed in the ipsilateral SC. Conclusions: Optic nerve crush induces damage in both the RGC layer and the superior colliculus. p38 and JNK activation are differently modulated by optic nerve crush, and might play different roles in neuronal death in the retina and superior colliculus.Item PROTECTIVE EFFECT OF JNK INHIBITION IN RETINAL GANGLION CELLS AND IN RETINAL ISCHEMIA/REPERFUSION INJURY(2013-04-12) Kim, Byung-JinPurpose: The JNK (cJUN N-terminal kinase) signaling pathway plays an important role in various neuronal pathophysiologies. Using JNK inhibitor SP600125, we examined involvement of the JNK pathway in cultured retinal ganglion cell (RGC) death and in mouse retinal ischemia/reperfusion (I/R) injury. Methods: The in vitro effects of of several JNK inhibitors were evaluated in cultured adult rat retinal cells enriched in RGCs. Cytotoxicity was induced by glutamate or trophic factor withdrawal. Survival of RGCs was assessed by counting Thy-1 postive cells. Retinal I/R was induced in female C57BL/6J mice by raising the intraocular pressure to 120 mmHg for 60 min followed by reperfusion. SP600125 (5, 15, 30 mg/kg) was administered intraperitoneally once daily for 28 days starting at 2 h prior to injury. At various time points after I/R, phosphorylation of JNK and cJun was examined by immunoblotting of retinal proteins. The thickness of retinal layers and cell numbers in ganglion cell layer (GCL) were monitored using H&E stained retinal cross sections, and retinal function was measured by scotopic ERG. Results: SP600125 dose-dependently and significantly (p<0.05) completely protected against glutamate- and trophic factor withdrawal-induced cultured RGC cell death. In the I/R model, phosphorylation of JNK and cJun in retina was significantly (p<0.05) increased at 1 h after injury. I/R injury significantly (p<0.05) decreased the thickness of retinal layers, including whole retina (-23.2 ± 5.7%), inner plexiform layer (-38.0 ± 6.7%), and inner nuclear layer (-25.1 ± 7.4 %) and cell numbers in GCL (-30.0 ± 5.6%). Importantly, administration of all three doses of SP600125 protected against all these degenerative morphological changes (p<0.05). In addition, SP600125 administration also significantly (p<0.05) protected against I/R-induced reduction in b-wave amplitude at 3, 7, 14, 21 and 28 days after injury. Conclusions: Our results demonstrated involvement of the JNK pathway in retinal degeneration in both in vitro and in vivo models and suggest that JNK inhibitors may be a useful therapeutic strategy for neuroprotection in the retina.