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. 2017 May;42(5):1449-1458.
doi: 10.1007/s11064-017-2201-4. Epub 2017 Feb 16.

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

Pei Wu  1 , Yuchen Li  1 , Shiyi Zhu  1 , Chunlei Wang  1 , Jiaxing Dai  1 , Guang Zhang  1 , Bingjie Zheng  1 , Shancai Xu  1 , Ligang Wang  1 , Tongyu Zhang  1 , PeiQuan Zhou  1 , John H Zhang  2 , Huaizhang Shi  3
Affiliations

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

Pei Wu et al. Neurochem Res. 2017 May.

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(Ser616), 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.

Keywords: Early brain injury; Mdivi-1; Mitochondrial fission; Oxidative stress; Subarachnoid hemorrhage.

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