title: Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.
abstract: OBJECTIVE
  Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors γ confer neuroprotection in models of cerebral ischemia, it is not known whether this effect extends to white matter protection. This study tested the hypothesis that the peroxisome proliferator-activated receptors γ agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion.
  
  
  METHODS
  Male adult C57/BL6 mice (25-30 g) were subjected to 60-minute middle cerebral artery occlusion and reperfusion. Rosiglitazone (3 mg/kg) was injected intraperitoneally once daily for 14 days beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated ≤21 days after middle cerebral artery occlusion. Immunostaining was used to assess infarct volume, myelin loss, and microglial activation. Bromodeoxyuridine (BrdU) was injected for measurements of proliferating NG2(+) oligodendrocyte precursor cells (OPCs) and newly generated adenomatous polyposis coli(+) oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization.
  
  
  RESULTS
  Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21 days after middle cerebral artery occlusion. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after middle cerebral artery occlusion. Rosiglitazone treatment also reduced the numbers of Iba1(+)/CD16(+) M1 microglia and increased the numbers of Iba1(+)/CD206(+) M2 microglia after stroke. Glial culture experiments confirmed that rosiglitazone promoted oligodendrocyte differentiation, perhaps by promoting microglial M2 polarization.
  
  
  CONCLUSIONS
  Rosiglitazone treatment improves long-term white matter integrity after cerebral ischemia, at least, in part, by promoting oligodendrogenesis and facilitating microglial polarization toward the beneficial M2 phenotype.
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Lijuan
authors.initials: L
authors.lastname: Han
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Leilei
authors.initials: L
authors.lastname: Mao
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.). chenj2@upmc.edu xuyun20042001@aliyun.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.).
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: From the Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P.R. China (L.H., Y.X.); Center of Cerebrovascular Disease Research, Department of Neurology, University of Pittsburgh School of Medicine, PA (L.H., W.C., L.M., X.H., J.C.); State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China (J.L., P.L., X.H., J.C.); Department of Neurology, Multiple Sclerosis Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China (W.C.); Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA (R.K.L.); and Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA (X.H., J.C.). chenj2@upmc.edu xuyun20042001@aliyun.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009836:Oligodendroglia / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects*; D015424:Reperfusion; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D066127:White Matter / Q000187:drug effects* / Q000473:pathology
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: bromodeoxyuridine; inflammation; polarization; stroke; white matter