Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.

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.

• Authors: Lijuan Han, Wei Cai, Leilei Mao, Jia Liu, Peiying Li, Rehana K Leak, Yun Xu, Xiaoming Hu, Jun Chen
• Journal: Stroke (Stroke) Vol. 46 Issue 9 Pg. 2628-36 (Sep 2015) ISSN: 1524-4628 [Electronic] United States
• PMID: 26243225 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• PPAR gamma
• Thiazolidinediones
• Rosiglitazone

Topics

• Animals
• Brain Ischemia (drug therapy)
• Disease Models, Animal
• Infarction, Middle Cerebral Artery (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects)
• Oligodendroglia (drug effects)
• PPAR gamma (agonists)
• Recovery of Function (drug effects)
• Reperfusion
• Rosiglitazone
• Thiazolidinediones (administration & dosage, pharmacology)
• White Matter (drug effects, pathology)