Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion.
Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion.
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DOI：
10.1016/j.neuroscience.2010.07.063
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发表时间：
2010-10-27
期刊：
影响因子：
3.3
通讯作者：
Sundararajan, S.
中科院分区：
文献类型：
--
作者：
Gamboa, J.;Blankenship, D. A.;Niemi, J. P.;Landreth, G. E.;Karl, M.;Hilow, E.;Sundararajan, S.
Stroke is a leading cause of death and disability but has limited therapeutic options. Thiazolidinediones (TZDs), agonists for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)γ, reduce infarct volume and improve neurologic function following transient middle cerebral artery occlusion (MCAO) in rats. Translation of these findings into clinical therapy will require careful assessment of dosing paradigms and effective time windows for treatment. Understanding the mechanisms by which TZDs protect the brain provides insight into how time windows for neuroprotection might be extended. We find that two TZDs, pioglitazone and rosiglitazone, significantly reduce infarct volume at doses similar to those used clinically (1 mg/kg for pioglitazone and 0.1 mg/kg for rosiglitazone). We also find that pioglitazone reduces infarction volume in a transient, but not a permanent MCAO model suggesting that reperfusion plays an important role in TZD mediated neuroprotection. Since PPARγ agonists reduce inflammation and oxidative stress, both of which are exacerbated by reperfusion, we hypothesized that TZDs would be most effective if administered prior to reperfusion. We administered TZDs three hours after MCAO and found that infarction volume and neurologic function are significantly improved in animals reperfused at three hours and fifteen minutes (after TZD treatment), but not in animals reperfused at two hours (before TZD treatment) when assessed either twenty-four hours or three weeks after MCAO. While TZDs reduce intercellular adhesion molecule (ICAM) expression to a similar extent regardless of the time of reperfusion, leukocyte entry into brain parenchyma is more dramatically reduced when reperfusion is delayed until after drug treatment. The finding that delaying reperfusion until after TZD treatment is beneficial despite a longer period of ischemia, is dramatic given the widely held view that duration of ischemia is the most important determinate of injury.
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DOI：
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