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

• Published in: Neurochemical research 2017-05, Vol.42 (5), p.1449-1458
• Main Authors: Wu, Pei, Li, Yuchen, Zhu, Shiyi, Wang, Chunlei, Dai, Jiaxing, Zhang, Guang, Zheng, Bingjie, Xu, Shancai, Wang, Ligang, Zhang, Tongyu, Zhou, PeiQuan, Zhang, John H., Shi, Huaizhang
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain Injuries - pathology; Cell Biology; Dynamins - antagonists & inhibitors; Dynamins - metabolism; Male; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - physiology; Neurochemistry; Neurology; Neurosciences; Original Paper; Oxidative Stress - drug effects; Oxidative Stress - physiology; Quinazolinones - pharmacology; Quinazolinones - therapeutic use; Rats; Rats, Wistar; Subarachnoid Hemorrhage - drug therapy; Subarachnoid Hemorrhage - metabolism; Subarachnoid Hemorrhage - pathology
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-017-2201-4

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.