Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion

Abstract

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

T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities

“…Therefore, preserving PPARγ activity by T33 treatment from the start of OGD is crucial in reducing inflammatory responses during ischemia and could also contribute to the late curtailed inflammatory cascades during reperfusion in the current ischemic core model. This result coincides with a recent in vivo study demonstrating that the administration of TZDs after reperfusion does not exert a neuroprotective effect toward ischemia [41] . However, we cannot rule out that non-PPARγ dependent pathways may be involved in reserving I-κBα protein levels by T33, because it still remains unknown how PPARγ activation influences eIF-2α phosphorylation.…”

A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats

“…Injected drug dose was the same or similar to that used by other investigators in different CNS models. For instance, Gamboa et al (2010) explored the effects of i.p. injected Fig.…”

“…Although TZDs were originally approved for treating non-insulindependent diabetes mellitus, their effects in different central nervous system (CNS) injury models like cerebral ischemia (Collino et al, 2006;Gamboa et al, 2010;Lee et al, 2008;Schmerbach et al, 2008;Sundararajan et al, 2005;Tureyen et al, 2007;Zhao et al, 2005), autoimmune encephalomyelitis (Diab et al, 2002;Feinstein et al, 2002), spinal cord injury (McTigue et al, 2007), Parkinson's (Breidert et al, 2002;Dehmer et al, 2004) and Alzheimer's (Heneka et al, 2005) diseases, amyotrophic lateral sclerosis (Kiaei et al, 2005;Schütz et al, 2005) and seizures (Abdallah, 2010;Okada et al, 2006;Sun et al, 2008;Yu et al, 2008) [also reviewed in Heneka and Landreth (2007), Kapadia et al (2008) and Sundararajan et al (2006)] were investigated and promising neuroprotective results were obtained.…”

Role of peroxisome proliferator‐activated receptors in stroke prevention and therapy—The best is yet to come?

“…Over the years PPAR-γ agonists have been shown to inhibit the whole spectrum of pro-inflammatory mediators in ischemic stroke models. In MCAO model pioglitazone has been demonstrated to inhibit COX-1 and COX-2 (Zhao, Patzer, Herdegen, Gohlke, & Culman, 2006), NF-kb (Zhang et al, 2011), IL-1β (Glatz et al, 2010), and ICAM (Gamboa et al, 2010).…”