PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury.
PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury.
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DOI：
10.3390/biom12101352
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发表时间：
2022-09-23
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
普列克底物蛋白同源结构域和富含亮氨酸的重复蛋白磷酸酶（PHLPP）敲除小鼠在中风、创伤性脑损伤（TBI）后具有改善的结果，并且在血管损伤后具有减少的适应不良的血管重塑。因此，小分子PHLPP抑制剂具有改善多种病症中的神经学结果的潜力。关于已知的实验性PHLPP抑制剂的功效的数据很少，并且并非所有抑制剂都适用于靶向急性脑损伤。在此，我们评估了几种先前未探索用于神经保护的PHLPP抑制剂（NSC 13378、NSC 25247和NSC 74429），这些抑制剂具有靶向中枢神经系统（CNS）的有利预测化学。在星形孢菌素（细胞凋亡）、谷氨酸（兴奋性毒性）和过氧化氢（坏死/氧化应激）中的神经元培养研究揭示，微摩尔浓度的NSC 74429是最具神经保护性的。随后在窒息性心脏骤停的大鼠模型和严重TBI的小鼠模型中进行的测试显示，连续给药lmg/kg的NSC 74429 3天改善了两种模型中的海马存活率。总之，NSC 74429在多种损伤机制中具有神经保护作用。未来的药代动力学和药效学（PK/PD）研究是必要的，以优化给药，机制研究需要确定由PHLPP 1/2抑制介导的神经保护的百分比，或潜在的PHLPP非依赖性靶点的调节。
Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury. Here, we assessed several PHLPP inhibitors not previously explored for neuroprotection (NSC13378, NSC25247, and NSC74429) that had favorable predicted chemistries for targeting the central nervous system (CNS). Neuronal culture studies in staurosporine (apoptosis), glutamate (excitotoxicity), and hydrogen peroxide (necrosis/oxidative stress) revealed that NSC74429 at micromolar concentrations was the most neuroprotective. Subsequent testing in a rat model of asphyxial cardiac arrest, and in a mouse model of severe TBI, showed that serial dosing of 1 mg/kg of NSC74429 over 3 days improved hippocampal survival in both models. Taken together, NSC74429 is neuroprotective across multiple insult mechanisms. Future pharmacokinetic and pharmacodynamic (PK/PD) studies are warranted to optimize dosing, and mechanistic studies are needed to determine the percentage of neuroprotection mediated by PHLPP1/2 inhibition, or potentially from the modulation of PHLPP-independent targets.
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影响因子：
8.3
作者：
Bosetti F;Koenig JI;Ayata C;Back SA;Becker K;Broderick JP;Carmichael ST;Cho S;Cipolla MJ;Corbett D;Corriveau RA;Cramer SC;Ferguson AR;Finklestein SP;Ford BD;Furie KL;Hemmen TM;Iadecola C;Jakeman LB;Janis S;Jauch EC;Johnston KC;Kochanek PM;Kohn H;Lo EH;Lyden PD;Mallard C;McCullough LD;McGavern LM;Meschia JF;Moy CS;Perez-Pinzon MA;Ramadan I;Savitz SI;Schwamm LH;Steinberg GK;Stenzel-Poore MP;Tymianski M;Warach S;Wechsler LR;Zhang JH;Koroshetz W
通讯作者：
Koroshetz W
影响因子：
8.8
作者：
Janata, Andreas;Magnet, Ingrid A. M.;Kochanek, Patrick M.
通讯作者：
Kochanek, Patrick M.
影响因子：
2.9
作者：
McNeill-Blue, Charlesene;Wetmore, Barbara A.;Merrick, B. Alex
通讯作者：
Merrick, B. Alex
影响因子：
16.2
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
影响因子：
8
作者：
Higgins, Gavin C.;Beart, Philip M.;Nagley, Phillip
通讯作者：
Nagley, Phillip