Lijuan Han1, Wei Cai1, Leilei Mao1, Jia Liu1, Peiying Li1, Rehana K Leak1, Yun Xu2, Xiaoming Hu1, Jun Chen2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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: Robin J M Franklin; Charles Ffrench-Constant; Veronique E Miron; Amanda Boyd; Jing-Wei Zhao; Tracy J Yuen; Julia M Ruckh; Jennifer L Shadrach; Peter van Wijngaarden; Amy J Wagers; Anna Williams Journal: Nat Neurosci Date: 2013-07-21 Impact factor: 24.884
Authors: Kanako Itoh; Takakuni Maki; Akihiro Shindo; Naohiro Egawa; Anna C Liang; Naoki Itoh; Eng H Lo; Josephine Lok; Ken Arai Journal: Neurosci Res Date: 2015-12-14 Impact factor: 3.304