PMID- 30355111
OWN - NLM
STAT- MEDLINE
DCOM- 20190910
LR  - 20191001
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Print)
IS  - 0039-2499 (Linking)
VI  - 49
IP  - 10
DP  - 2018 Oct
TI  - Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits 
      After Cerebral Ischemia.
PG  - 2453-2463
LID - 10.1161/STROKEAHA.118.021452 [doi]
AB  - Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity 
      that exacerbates ischemic brain injury and worsens functional outcome after 
      stroke. T2DM is known to aggravate white matter (WM) impairment, but the 
      underlying mechanism is not completely understood. This study was designed to 
      test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both 
      oligodendrogenesis and beneficial microglia/macrophage responses. Methods- 
      Permanent distal middle cerebral artery occlusion was performed in wild-type, 
      homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open 
      field, and Morris water maze tests were used to assess neurobehavioral outcomes. 
      Neuronal tissue loss, WM damage, oligodendrogenesis, and microglia/macrophage 
      responses were evaluated up to 35 days after stroke. The functional integrity of 
      WM was measured by electrophysiology. Primary microglia-oligodendrocyte 
      cocultures were used for additional mechanistic studies. Results- T2DM 
      exacerbated structural damage and impaired conduction of compound action 
      potentials in WM 35 days after stroke. The deterioration in WM integrity 
      correlated with poor sensorimotor performance. Furthermore, T2DM impaired the 
      proliferation of oligodendrocyte precursor cells and the generation of new 
      myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage 
      phenotype toward the proinflammatory modality. Coculture studies confirmed that 
      microglia/macrophage polarization toward the proinflammatory phenotype under high 
      glucose conditions suppressed oligodendrocyte precursor cell differentiation. 
      Conclusions- Deterioration of WM integrity and impairments in oligodendrogenesis 
      after stroke are associated with poor long-term functional outcomes in 
      experimental diabetes mellitus. High glucose concentrations may shift 
      microglia/macrophage polarization toward a proinflammatory phenotype, 
      significantly impairing oligodendrocyte precursor cell differentiation and WM 
      repair.
FAU - Ma, Shubei
AU  - Ma S
AD  - From the Institute of Cerebrovascular Disease Research and Department of 
      Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China (S.M., 
      Y.L.).
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Wang, Jianyi
AU  - Wang J
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Wang, Yanling
AU  - Wang Y
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Dai, Xuejiao
AU  - Dai X
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Xu, Fei
AU  - Xu F
AD  - Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh 
      Healthcare System, PA (F.X., X.H., J.C.).
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Gao, Xuguang
AU  - Gao X
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Johnson, Joycelyne
AU  - Johnson J
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Xu, Na
AU  - Xu N
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Leak, Rehana K
AU  - Leak RK
AD  - Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 
      (R.K.L.).
FAU - Hu, Xiaoming
AU  - Hu X
AD  - Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh 
      Healthcare System, PA (F.X., X.H., J.C.).
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
FAU - Luo, Yumin
AU  - Luo Y
AD  - From the Institute of Cerebrovascular Disease Research and Department of 
      Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China (S.M., 
      Y.L.).
FAU - Chen, Jun
AU  - Chen J
AD  - Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh 
      Healthcare System, PA (F.X., X.H., J.C.).
AD  - Pittsburgh Institute of Brain Disorders and Recovery, and Department of 
      Neurology, University of Pittsburgh School of Medicine, PA (S.M., J.W., Y.W., 
      X.D., F.X., X.G., J.J., N.X., X.H., J.C.).
LA  - eng
GR  - I01 RX000420/RX/RRD VA/United States
GR  - R01 NS045048/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
SB  - IM
MH  - Animals
MH  - Brain Ischemia/complications/*pathology
MH  - Diabetes Mellitus, Type 2/*complications
MH  - Disease Models, Animal
MH  - Infarction, Middle Cerebral Artery/complications/pathology
MH  - Macrophages/metabolism/pathology
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microglia/metabolism/pathology
MH  - Oligodendroglia/pathology
MH  - Stroke/complications/pathology/*physiopathology
MH  - White Matter/*pathology
PMC - PMC6205761
MID - NIHMS1504132
OTO - NOTNLM
OT  - diabetes mellitus
OT  - macrophages
OT  - microglia
OT  - stroke
OT  - white matter
EDAT- 2018/10/26 06:00
MHDA- 2019/09/11 06:00
PMCR- 2019/10/01
CRDT- 2018/10/26 06:00
PHST- 2018/10/26 06:00 [entrez]
PHST- 2018/10/26 06:00 [pubmed]
PHST- 2019/09/11 06:00 [medline]
PHST- 2019/10/01 00:00 [pmc-release]
AID - 10.1161/STROKEAHA.118.021452 [doi]
PST - ppublish
SO  - Stroke. 2018 Oct;49(10):2453-2463. doi: 10.1161/STROKEAHA.118.021452.