Abstract:
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.
摘要:
Pleckstrin同源域和富含亮氨酸的重复蛋白磷酸酶(PHLPP)敲除小鼠在中风后的预后得到改善,创伤性脑损伤(TBI),血管损伤后适应不良的血管重塑减少。因此,小分子PHLPP抑制剂有可能在多种情况下改善神经系统预后.关于已知的实验性PHLPP抑制剂的功效的数据很少,并不是所有的都适合针对急性脑损伤。这里,我们评估了几种以前没有研究过的用于神经保护的PHLPP抑制剂(NSC13378,NSC25247和NSC74429),这些抑制剂具有良好的预测化学靶向中枢神经系统(CNS).星形孢菌素(凋亡)的神经元培养研究,谷氨酸(兴奋毒性),和过氧化氢(坏死/氧化应激)表明,微摩尔浓度的NSC74429是最神经保护的。随后在窒息心脏骤停的大鼠模型中进行测试,在严重TBI的小鼠模型中,显示在两个模型中,连续给药1mg/kg的NSC74429在3天内改善了海马存活率。一起来看,NSC74429是跨多种损伤机制的神经保护性。未来的药代动力学和药效学(PK/PD)研究是必要的,以优化剂量,和机制研究是必要的,以确定由PHLPP1/2抑制介导的神经保护的百分比,或可能来自PHLPP非依赖性靶标的调节。