Cell lines

Primary cortical neuron(PCN)

Preparation Method

PCNs were treated with Mdivi-1 (from 0.001 nM to 1 mM) dissolved in 0.1% DMSO 1 h before scratch cell injury. The release of lactate dehydrogenase(LDH)into the culture media was measured 6 h after scratch cell injury.

Reaction Conditions

0.001 nM to 1 mM for 1hour

Applications

Using LDH assay, exposing PCNs to scratch cell injury with Mdivi-1 (100 μM and 1 mM) resulted in significant dose-dependent inhibition of cell death. Hence the range of the optimum concentration was from 10 μM to 100 μM.

Animal models

male ICR mice

Preparation Method

For the mice treated with Mdivi-1 (3 mg/kg), dynamin-related protein 1 (Drp1) inhibitor, was administered by intraperitoneal injection 10 min after TBI. Mdivi-1 was dissolved in 0.01 M PBS. Vehicle animals received an intraperitoneal injection of 0.01 M PBS.

Dosage form

Intraperitoneal injection, 3 mg/kg

Applications

Treatment with Mdivi-1 accelerated the recovery of motor functional outcome on days 3-5 post-TBI. After injury, animals subjected to Mdivi-1 treatment demonstrated a significant decrease in the latencies, relative to vehicle mice on days 15 and 16, thereby Mdivi-1 treatment could result in cognitive functional recovery.

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.