title: A novel imidazopyridine derivative, X22, prevents the retinal ischemia-reperfusion injury via inhibition of MAPKs.
abstract: Inflammation is a pathological hallmark of ischemia reperfusion (I/R) injury. The present study was conducted to explore the ability of a new anti-inflammatory compound, X22, to attenuate retinal I/R injury via cytokine-inhibitory mechanism. For the in vitro experiment, ARPE-19 cells were pretreated with X22 (5 or 10 μM) or saline for 2 h, followed by stimulation with tert-butyl hydroperoxide (TBHP, 1000 μM) for an indicated amount of time. The expression of inflammatory mediators, cell viability, and cell apoptosis were evaluated. For the in vivo experiment, the rats were randomized to receive treatment with saline or X22 (0.1 μM/kg, 3 μL) before the induction of I/R injury. Histological evaluation, apoptosis of retinal cells, macrophage infiltration, and retina functional changes were further determined. Our data showed that pretreatment with X22 significantly inhibited TBHP-induced inflammatory cytokine expression in ARPE-19 cells. The anti-inflammatory activity of X22 may be associated with its inhibition on MAPKs, rather than NF-κB. Subsequently, our data proved that TBHP induced apoptosis in ARPE-19 cells, while pretreatment of X22 significantly suppressed TBHP-caused ARPE-19 apoptosis. Finally, the in vivo data revealed that X22 administration maintained better inner retinal layer structures, reduced apoptosis of retinal ganglion cell, and improved retinal function in retinal I/R rat models, which were accompanied with a remarkable decrease in retinal macrophage infiltration. These results suggest that the novel compound X22 is a potential agent for the treatment of retinal I/R-related diseases via the MAPKs-targeting anti-inflammatory mechanism and deserves the further development.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Ren
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Shanmei
authors.initials: S
authors.lastname: Xu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zongming
authors.initials: Z
authors.lastname: Song
authors.affiliation: The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: wuwencan118@163.com.
authors.forename: Wencan
authors.initials: W
authors.lastname: Wu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: yi.wang1122@gmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D012164:Retinal Diseases / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007093:Imidazoles; D011725:Pyridines; C000600451:X22 compound; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Apoptosis; Inflammation; MAPKs; NF-κB; Retinal ischemia-reperfusion injury