PMID- 30779914
OWN - NLM
STAT- MEDLINE
DCOM- 20200221
LR  - 20211204
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 317
DP  - 2019 Jul
TI  - Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 
      pathway after subarachnoid hemorrhage in rats.
PG  - 1-9
LID - S0014-4886(19)30022-6 [pii]
LID - 10.1016/j.expneurol.2019.02.009 [doi]
AB  - BACKGROUND AND PURPOSE: Mitochondrial dysfunction is involved in the mechanism of 
      early brain injury (EBI) following subarachnoid hemorrhage (SAH). Blood-brain 
      barrier disruption is a devastating outcome in the early stage of SAH. In this 
      study, we aimed to investigate the role of a mitochondria-related drug 
      Mitoquinone (MitoQ) in blood-brain barrier disruption after SAH in rats. METHODS: 
      A total of 181 male Sprague-Dawley SAH rats with the endovascular perforation 
      model were utilized. Intraperitoneal MitoQ was given 1 h (h) post-SAH. 
      Cerebroventricular ML385, an inhibitor of NF-E2-related factor 2 (Nrf2) and Small 
      interfering ribonucleic acid (siRNA) for Prohibitin 2 (PHB2) were injected 
      respectively 24 h and 48 h before SAH. Neurological function evaluation was 
      performed before sacrifice. SAH grade was measured during the sacrifice of each 
      animal. Brain water content was performed at 24 h. Co-immunoprecipitation was 
      used to demonstrate the relationship of proteins Nrf2 and PHB2. Mitochondrial and 
      cytoplasmic fractions were gathered using mitochondria isolation kits. Pathway 
      related proteins were investigated with Western blot and immunofluorescence 
      staining. Transmission electron microscopy was performed for mitochondrial 
      morphology. RESULTS: Expression of Nrf2 levels peaked at the 3 h time point 
      following SAH and then decreased to normal levels at 24 h, while PHB2 and Optic 
      Atrophy 1 (OPA1) decreased at 24 h and 72 h after SAH compared with the Sham 
      group. MitoQ treatment attenuated neurological deficits and brain edema, thereby 
      resulting in a decreased expression of Albumin, while an increase of Nrf2, PHB2, 
      OPA1 and Claudin-5 proteins compared with SAH + vehicle group. With 
      co-immunoprecipitation, Nrf2 and PHB2 were further demonstrated to show their 
      interaction. And MitoQ administration lead to more binding of the two proteins. 
      ML385 abolished the effects of MitoQ on neurobehavior and protein levels 
      post-SAH. Similarly, PHB2 siRNA reversed the neuroprotection of MitoQ 
      administration with the decreased expression of PHB2 and OPA1 after SAH. Further, 
      MitoQ treatment improved mitochondrial morphology after SAH with an increase of 
      PHB2 and OPA1 in mitochondrial extraction. CONCLUSIONS: MitoQ attenuates 
      blood-brain barrier disruption via Nrf2/PHB2/OPA1 pathway after SAH in rats. 
      MitoQ may serve as a potential therapeutic strategy for SAH patients.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Zhang, Tongyu
AU  - Zhang T
AD  - Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, Heilongjiang, China; Department of Physiology and 
      Pharmacology, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma 
      Linda, CA 92354, USA.
FAU - Xu, Shancai
AU  - Xu S
AD  - Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, Heilongjiang, China.
FAU - Wu, Pei
AU  - Wu P
AD  - Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, Heilongjiang, China; Department of Physiology and 
      Pharmacology, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma 
      Linda, CA 92354, USA.
FAU - Zhou, Keren
AU  - Zhou K
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Wu, Lingyun
AU  - Wu L
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Xie, Zhiyi
AU  - Xie Z
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Xu, Weilin
AU  - Xu W
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Luo, Xu
AU  - Luo X
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Li, Peng
AU  - Li P
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Ocak, Umut
AU  - Ocak U
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Ocak, Pinar Eser
AU  - Ocak PE
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Travis, Zachary D
AU  - Travis ZD
AD  - Department of Earth and Biological Sciences, Loma Linda University, Loma Linda, 
      CA, USA.
FAU - Tang, Jiping
AU  - Tang J
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA.
FAU - Shi, Huaizhang
AU  - Shi H
AD  - Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, Heilongjiang, China. Electronic address: 
      huaizhangshi@126.com.
FAU - Zhang, John H
AU  - Zhang JH
AD  - Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus 
      St, Risley Hall, Room 219, Loma Linda, CA 92354, USA. Electronic address: 
      jhzhang@llu.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190216
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Nfe2l2 protein, rat)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (Prohibitins)
RN  - 0 (Repressor Proteins)
RN  - 1339-63-5 (Ubiquinone)
RN  - 47BYS17IY0 (mitoquinone)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (Opa1 protein, rat)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/*drug effects/metabolism/pathology
MH  - GTP Phosphohydrolases/drug effects/metabolism
MH  - Male
MH  - NF-E2-Related Factor 2/drug effects/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Organophosphorus Compounds/*pharmacology
MH  - Prohibitins
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Repressor Proteins/drug effects/metabolism
MH  - Signal Transduction/*drug effects
MH  - Subarachnoid Hemorrhage/*metabolism/pathology
MH  - Ubiquinone/*analogs & derivatives/pharmacology
OTO - NOTNLM
OT  - Blood-brain barrier disruption
OT  - Mitoquinone
OT  - NF-E2-related factor 2
OT  - Optic atrophy 1
OT  - Prohibitin 2
OT  - Subarachnoid hemorrhage
EDAT- 2019/02/20 06:00
MHDA- 2020/02/23 06:00
CRDT- 2019/02/20 06:00
PHST- 2018/12/13 00:00 [received]
PHST- 2019/02/11 00:00 [revised]
PHST- 2019/02/15 00:00 [accepted]
PHST- 2019/02/20 06:00 [pubmed]
PHST- 2020/02/23 06:00 [medline]
PHST- 2019/02/20 06:00 [entrez]
AID - S0014-4886(19)30022-6 [pii]
AID - 10.1016/j.expneurol.2019.02.009 [doi]
PST - ppublish
SO  - Exp Neurol. 2019 Jul;317:1-9. doi: 10.1016/j.expneurol.2019.02.009. Epub 2019 Feb 
      16.