Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.
Chu
Kon
K
Department of Neurology, Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Lee
Soon-Tae
ST
Koo
Ja-Seong
JS
Jung
Keun-Hwa
KH
Kim
Eun-Hee
EH
Sinn
Dong-In
DI
Kim
Jeong-Min
JM
Ko
Song-Yi
SY
Kim
Se-Jeong
SJ
Song
Eun-Chol
EC
Kim
Manho
M
Roh
Jae-Kyu
JK
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D053222:Fas Ligand Protein; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000378:metabolism
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D048069:Tumor Necrosis Factors; D000077154:Rosiglitazone; D052250:Nitric Oxide Synthase Type III; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases