title: Peroxisome proliferator-activated receptor-γ agonist pioglitazone ameliorates white matter lesion and cognitive impairment in hypertensive rats.
abstract: OBJECTIVE
  Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats.
  
  
  METHODS
  Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected.
  
  
  RESULTS
  Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1β and TNF-α in the white matter.
  
  
  CONCLUSIONS
  Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.
authors.affiliation: Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Lin-Fang
authors.initials: LF
authors.lastname: Lan
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.forename: Xiao-Tan
authors.initials: XT
authors.lastname: Ji
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Fan
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000077205:Pioglitazone; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*; D066127:White Matter / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D018697:Nootropic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Hypertensive white matter lesion; Inflammation; Peroxisome proliferator-activated receptor-γ; Pioglitazone; Small vessel disease