Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress

Abstract

Mdivi-1 is a selective inhibitor of mitochondrial fission protein, Drp1, and can penetrate the blood-brain barrier. Previous studies have shown that Mdivi-1 improves neurological outcomes after ischemia, seizures and trauma but it remains unclear whether Mdivi-1 can attenuate early brain injury after subarachnoid hemorrhage (SAH). We thus investigated the therapeutic effect of Mdivi-1 on early brain injury following SAH. Rats were randomly divided into four groups: sham; SAH; SAH + vehicle; and SAH + Mdivi-1. The SAH model was induced by standard intravascular perforation and all of the rats were subsequently sacrificed 24 h after SAH. Mdivi-1 (1.2 mg/kg) was administered to rats 30 min after SAH. We found that Mdivi-1 markedly improved neurologic deficits, alleviated brain edema and BBB permeability, and attenuated apoptotic cell death. Mdivi-1 also significantly reduced the expression of cleaved caspase-3, Drp1 and p-Drp1, attenuated the release of Cytochrome C from mitochondria, inhibited excessive mitochondrial fission, and restored the ultra-structure of mitochondria. Furthermore, Mdivi-1 reduced levels of MDA, 3-NT, and 8-OHdG, and improved SOD activity. Taken together, our data suggest that Mdivi-1 exerts neuroprotective effects against cell death induced by SAH and the underlying mechanism may be inhibition of Drp1-activated mitochondrial fission and oxidative stress.

Propoxyphene Mediates Oxyhemoglobin-Induced Injury in Rat Cortical Neurons Through Up-Regulation of Active-β-Catenin

“…The expression of c-Myc can restore the mitochondrial volume and induce increased fusion (Graves et al, 2012). Excessive mitochondrial fission has been shown to be involved in the EBI stage following SAH (Wu et al, 2017). In the present study, silencing b-catenin abrogated the protective effect of Pro against the mitochondrial fission phenotype induced by OxyHb.…”

“…c-Myc, a down-stream protein of Wnt/b-catenin signaling, contributes to the fusion of mitochondria (Graves et al, 2012). Previous studies have shown that excessive mitochondrial fission is involved in the EBI stage following SAH (Wu et al, 2017). This study, therefore, aims to investigate the protective role of propoxyphene against OxyHb-induced cell apoptosis in primary cortical neurons.…”

“…Mitochondrial fission produces dysfunctional organelles, and fusion can maintain the integrity of mitochondria. Mitochondrial disruption and fission have been shown to occur after SAH (Wu et al, 2017). Furthermore, Wnt/b-catenin signaling is responsible for an increase in membrane fusion (Graves et al, 2012).…”

Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity

“…The role of excessive ROS generation in oxidative stress and cardiovascular diseases is commonly accepted [ 30 ], and an appropriate balance between ROS and antioxidants is essential for vasoconstriction [ 31 ]. The effects of Mdivi-1 on oxidative stress are still controversial, although the antioxidative effects of Mdivi-1 are emphasized by most studies [ 28 , 32 ]. A slight increase of ROS level was observed in Mdivi-1-treated WT and Drp1 knockout mouse embryonic fibroblasts (MEFs) in the study by Bordt EA et al [ 13 ].…”

Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic‐ischaemic brain injury

“…However, a very recent study suggested that mdivi‐1 is a poor inhibitor of Drp1 and rather acts as a reversible mitochondrial complex I inhibitor and regulator of ROS production . Regardless, a number of studies have shown that mdivi‐1 improves outcome after OGD and abrogates brain injury after MCAO , subarachnoid haemorrhage , transient global ischaemia and traumatic brain injury .…”