Citation: Tsutsumi T, Iwao K, Hayashi H, et al. Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK activity. Invest Ophthalmol Vis Sci. 2016;57:6461-6473. DOI:10.1167/ iovs.16-19494 PURPOSE. The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. METHODS.The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-Daspartate (NMDA)-induced excitotoxicity. Additionally, the molecules associated with tranylcypromine treatment were assessed by microarray and immunoblot analysis. RESULTS.Tranylcypromine significantly suppressed neuronal cell death following glutamate neurotoxicity and oxidative stress. Microarray and immunoblot analyses revealed that p38 mitogen-activated protein kinase (MAPK)c was a key molecule involved in the neuroprotective mechanisms induced by tranylcypromine because the significant suppression of p38 MAPKc by glutamate was reversed by tranylcypromine. Moreover, although pharmacologic inhibition of the phosphorylation of the total p38 MAPKs interfered with neuroprotective effects of tranylcypromine, the specific inhibition of p38 MAPKa and p38 MAPKb did not influence RGC survival. This suggests that the non-p38 MAPKa/b isoforms have important roles in neuronal survival by tranylcypromine. Additionally, the intravitreal administration of tranylcypromine significantly saved RGC numbers in an in vivo glaucoma model employing NMDA-induced excitotoxicity.CONCLUSIONS. These findings indicate that tranylcypromine-induced transcriptional and epigenetic regulation modulated RGC survival via the promotion of p38 MAPKc activity. Therefore, pharmacologic treatments that suppress LSD1 activity may be a novel therapeutic strategy that can be used to treat neurodegenerative diseases.
Objective: The annual incidence of rhegmatogenous retinal detachment (RRD) in Kumamoto, Japan was previously evaluated in 1990. However, the incidence has not been evaluated during the last 20 years. The purpose of this study was to estimate the current incidence and epidemiologic characteristics of RRD in Kumamoto, Japan. Methods:The study was based on a retrospective chart review of hospital patients living in Kumamoto, Japan. All patients were treated for primary RRD by conventional surgery (pars plana vitrectomy and/or scleral buckling) at Kumamoto University Hospital or Ideta Eye Hospital between January 1, 2009, and December 31, 2011. Information on age, gender, refractive status, and history of cataract surgery was collected.Results: A total of 897 RRD patients were identified during the 3-year study period. The annual incidence of RRD was 16.5 (21.9 in males, 11.7 in females) per 100,000 people, with a peak incidence of 35.4 in the 50-59 years of age group. The incidence of RRD in males was 1.88 times (95% confidence interval, 1.56-2.29) higher than in females (P<0.0001). Prior cataract extraction was found in 14% of RRD eyes. Myopia (≤ −1 diopter [D]) was found in 54%, and high myopia (≤ −6 D) was found in 23%. The mean refraction status was −3.53 ± 3.94 D. The mean refractive status in patients younger than 50 years of age (−6.00 ± 3.33 D) was significantly higher than that in patients 50 years of age or older (−2.23 ± 3.61 D; P<0.001). The incidence of RRD in Kumamoto is expected to increase over the next 20 years in comparison to a previous study investigated in 1990. Conclusion:The annual incidence of RRD was dependent on age, gender, refraction status, and history of cataract surgery. Considering the growing elderly population, we expect that the incidence of RRD will continue to increase in Japan.
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