Peroxisome proliferator-activated receptor-γ (PPAR-γ) activation confers functional neuroprotection in global ischemia.
The neuroprotective effect of rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, has been investigated using both in vivo and in vitro models of global ischemia in CD1 mice. Behavioral tests were carried out prior to and at various times (up to 14 days) subsequent to bilateral common carotid artery occlusion followed by reperfusion. Mice at each time point were euthanized under anesthesia and the brain was removed, serially sliced and stained with 1% triphenyltetrazolium (TTC) to quantify infarct size. Administration of rosiglitazone (5 or 10 mg/kg, i.p.) 10 min prior to occlusion significantly reduced the postsurgical mortality rate (10-11 vs. 36%, P < 0.05). The higher dose of rosiglitazone (10 mg/kg) also significantly reduced the mean area of brain infarct at 1, 3, 7 and 14 days post-ischemia, reduced post-occlusion deficits in limb grasping and forelimb placing at various time points, and reduced total nitrite concentration in serum and brain homogenate at day 7 post-occlusion. To model global ischemia in vitro, coronal brain slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) in the presence of either glutamate (1 mM) or hydrogen peroxide (H(2)O(2)) (5 μM) for 30 min. Both H(2)O(2) and glutamate caused significant tissue damage, and co-incubation with rosiglitazone (5 μM) significantly reduced H(2)O(2)-induced damage but did not significantly reduce glutamate-induced brain damage in this model. Our observations provide further evidence for a neuroprotective effect of rosiglitazone in rodent models of ischemia.
Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PEI, Canada.
Zahra
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Fatehi-Hassanabad
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RA
Tasker
D000818:Animals; D004195:Disease Models, Animal; D006861:Hydrogen Peroxide / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000819:agonists / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000819:agonists / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006861:Hydrogen Peroxide