Mdivi-1 (Mitochondrial division inhibitor 1) inhibits traumatic brain injury (TBI)-induced dynamin-related protein 1(Drp1) up-regulation, autophagy dysfunction and mitophagy activation. Mdivi-1 decreased TBI-induced cell death and lesion volume [1,2].
Mdivi-1 is a selective Drp 1 inhibitor with IC50 value as 10 mμ[3]. Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24 h both in the basal state and under the conditions of scratch cell injury [1].
Mdivi-1 could significantly rescue neurons from death induced by seizures in a dose-dependent manner. In addition, the seizures increase Drp1 expression in hippocampus. These suggested that the up-regulation of Drp1 expression could be partially responsible for seizure-induced neuronal death. Moreover, CytC release, AIF translocation and caspase-3 activation may be involved in the protective mechanisms of mdivi-1 against seizure-induced neuronal death [4].
References:
[1]. Q. Wu, C. Gao, H. Wang, X. Zhang, et al. Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int. J. Biochem. Cell Biol., 94 (2018), pp. 44-55, 10.1016/j.biocel.2017.11.007
[2]. Q. Wu, S.X. Xia, Q.Q. Li, et al. Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res., 1630 (2016), pp. 134-143
[3]. D. Wu, A. Dasgupta, K.H. Chen, M. Neuber-Hess, J. Patel, T.E. Hurst, J.D. Mewburn, P.D.A. Lima, E. Alizadeh, A. Martin, M. Wells, V. Snieckus, S.L. Archer. Identification of novel dynamin-related protein 1 (Drp1) GTPase inhibitors: therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia-reperfusion injury.FASEB J., 34 (2020), pp. 1447-1464
[4]. Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q. A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. (2013b) Neurosci Lett 545: 64 -68.
Mdivi-1（线粒体分裂抑制剂 1）抑制创伤性脑损伤 (TBI) 诱导的动力蛋白相关蛋白 1 (Drp1) 上调、自噬功能障碍和线粒体自噬激活。 Mdivi-1 减少了 TBI 诱导的细胞死亡和损伤体积 [1,2]。
Mdivi-1 是一种选择性 Drp 1 抑制剂，IC50 值为 10 mμ[3]。 Mdivi-1 显着减轻了划痕损伤引起的细胞死亡、线粒体膜电位丧失、活性氧 (ROS) 产生和原代皮层神经元 (PCN) 中 ATP 的减少。此外，在基础状态和划痕细胞损伤条件下，溶酶体抑制剂氯喹 (CQ) 在 24 小时内消除了 Mdivi-1 诱导的自噬体积累减少和细胞死亡[1]。
Mdivi-1 可以剂量依赖性方式显着挽救神经元免于癫痫发作引起的死亡。此外，癫痫发作会增加海马体中 Drp1 的表达。这些表明 Drp1 表达的上调可能是癫痫发作引起的神经元死亡的部分原因。此外，CytC释放、AIF易位和caspase-3激活可能参与了mdivi-1对癫痫引起的神经元死亡的保护机制[4]。