Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury.
Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury.
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开发NADPH氧化酶2的改进和特异性抑制剂，以治疗创伤性脑损伤。
DOI：
10.1016/j.redox.2023.102611
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发表时间：
2023-04
期刊：
影响因子：
11.4
通讯作者：
Gallin, John I.
中科院分区：
文献类型：
--
作者：
Mason, Hannah;Rai, Ganesha;Kozyr, Arina;De Jonge, Nathaniel;Gliniewicz, Emily;Berg, Lars J.;Wald, Gal;Dorrier, Cayce;Henderson, Mark J.;Zakharov, Alexey;Dyson, Tristan;Audley, John;Pettinato, Anthony M.;Padilha, Elias Carvalho;Shah, Pranav;Xu, Xin;Leto, Thomas L.;Simeonov, Anton;Zarember, Kol A.;McGavern, Dorian B.;Gallin, John I.
NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis and other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) and other diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against xanthine oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI. A new NOX2 inhibitor, NCATS-SM7270, protects mice from mild traumatic brain injury. Knockout of NOX1 or NOX2 protects from injury while deletion of NOX4 increases it. NCATS-SM7270 partially reversed mTBI in NOX4KO mice.
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影响因子：
9.3
作者：
Dohi K;Ohtaki H;Nakamachi T;Yofu S;Satoh K;Miyamoto K;Song D;Tsunawaki S;Shioda S;Aruga T
通讯作者：
Aruga T
影响因子：
3.7
作者：
Eakin K;Baratz-Goldstein R;Pick CG;Zindel O;Balaban CD;Hoffer ME;Lockwood M;Miller J;Hoffer BJ
通讯作者：
Hoffer BJ
影响因子：
11.4
作者：
Ma MW;Wang J;Dhandapani KM;Wang R;Brann DW
通讯作者：
Brann DW
影响因子：
15.1
作者：
Ma MW;Wang J;Zhang Q;Wang R;Dhandapani KM;Vadlamudi RK;Brann DW
通讯作者：
Brann DW
影响因子：
6.6
作者：
Bernard, Karen;Thannickal, Victor J.
通讯作者：
Thannickal, Victor J.