TY - JOUR
T1 - Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress
AU - Wu, Pei
AU - Li, Yuchen
AU - Zhu, Shiyi
AU - Wang, Chunlei
AU - Dai, Jiaxing
AU - Zhang, Guang
AU - Zheng, Bingjie
AU - Xu, Shancai
AU - Wang, Ligang
AU - Zhang, Tongyu
AU - Zhou, Pei Quan
AU - Zhang, John H.
AU - Shi, Huaizhang
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - Early brain injury
KW - Mdivi-1
KW - Mitochondrial fission
KW - Oxidative stress
KW - Subarachnoid hemorrhage
KW - Rats, Wistar
KW - Rats
KW - Male
KW - Oxidative Stress/drug effects
KW - Animals
KW - Brain Injuries/drug therapy
KW - Mitochondrial Dynamics/drug effects
KW - Dynamins/antagonists & inhibitors
KW - Quinazolinones/pharmacology
KW - Subarachnoid Hemorrhage/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85013031365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013031365&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/c94d2d6e-764f-38bc-a09b-63da4ea08d89/
U2 - 10.1007/s11064-017-2201-4
DO - 10.1007/s11064-017-2201-4
M3 - Article
C2 - 28210956
SN - 0364-3190
VL - 42
SP - 1449
EP - 1458
JO - Neurochemical Research
JF - Neurochemical Research
IS - 5
ER -