Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs BLDV, Tampa, FL 33612, USA.
USF Health Heart Institute, Morsani College of Medicine, University of South Florida, 560 Channelside Dr, Tampa, FL 33602, USA.
Biomolecules. 2022 Sep 23;12(10):1352. doi: 10.3390/biom12101352.
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.
PHLPP 结构域和富含亮氨酸重复蛋白磷酸酶（PHLPP）敲除小鼠在中风、创伤性脑损伤（TBI）后具有更好的预后，并且在血管损伤后血管适应性重构减少。因此，小分子 PHLPP 抑制剂有可能改善多种情况下的神经预后。关于已知实验性 PHLPP 抑制剂的疗效数据很少，并非所有抑制剂都适合针对急性脑损伤。在这里，我们评估了几种以前未用于神经保护的 PHLPP 抑制剂（NSC13378、NSC25247 和 NSC74429），这些抑制剂具有针对中枢神经系统（CNS）的有利预测化学性质。在星形孢菌素（凋亡）、谷氨酸（兴奋性毒性）和过氧化氢（坏死/氧化应激）的神经元培养研究中，发现 NSC74429 在微摩尔浓度下具有最强的神经保护作用。随后在窒息性心脏骤停大鼠模型和严重 TBI 小鼠模型中的测试表明，3 天内连续给予 1mg/kg 的 NSC74429 可改善两种模型中的海马体存活。总之，NSC74429 在多种损伤机制下均具有神经保护作用。需要进行未来的药代动力学和药效学（PK/PD）研究以优化剂量，并需要进行机制研究以确定由 PHLPP1/2 抑制介导的神经保护的百分比，或者可能由 PHLPP 非依赖性靶标调节介导的神经保护的百分比。
