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

• Published in: Neuroscience Vol. 170; no. 3; pp. 846 - 857
• Main Authors: Gamboa, J, Blankenship, D.A, Niemi, J.P, Landreth, G.E, Karl, M, Hilow, E, Sundararajan, S
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 27.10.2010; Elsevier
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Blood Pressure - drug effects; Brain; Brain - blood supply; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Cell Adhesion Molecules - metabolism; cerebral ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fundamental and applied biological sciences. Psychology; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Leukocytes - drug effects; Male; Medical sciences; Neurology; neuroprotection; Neuroprotective Agents - administration & dosage; pioglitazone; PPARγ; Rats; Rats, Wistar; Regional Blood Flow - drug effects; Reperfusion - methods; rosiglitazone; Stroke - drug therapy; Thiazolidinediones - administration & dosage; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; immunoreactivity; nuclear factor κB; DMSO; high powered field; 15-deoxy-Δ(12,14)-prostaglandin J2; AP-1; stroke academic industry roundtable; STAIR; activator protein 1; mNSS; PPAR; SUMO1; PPRE; Cu/Zn; STAT-1; modified neurological severity score; US; PBS; NFκB; cycle threshold; IR; PPARγ; copper/zinc; pioglitazone; ROS; cerebral blood flow; SEM; Federal Drug Administration; peroxisome proliferator response element; standard error of the mean; PCR; HPF; FDA; magnetic resonance imaging; TTC; triphenyl tetrazolium chloride; MRI; United States; CBF; RXR; dimethyl sulfoxide; analysis of variance; ANOVA; cerebral ischemia; reactive oxygen species; peroxisome proliferator-activated receptor; polymerase chain reaction; computed tomography; MCAO; thiazolidinedione; ICAM; retinod X, receptor; signal transducers and activator of transcription 1; CT; neuroprotection; phosphate buffered saline; small ubiquitin-like modifier; rosiglitazone; PGJ2; intracellular adhesion molecule; middle cerebral artery occlusion; TZD; Neuroprotection; Nervous system diseases; Stroke; Pioglitazone; Central nervous system; Cardiovascular disease; Cerebral disorder; Encephalon; Vascular disease; Central nervous system disease; Brain ischemia; Rosiglitazone; Cerebrovascular disease
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.07.063

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 3 h after MCAO and found that infarction volume and neurologic function are significantly improved in animals reperfused at 3 h and 15 min (after TZD treatment), but not in animals reperfused at 2 h (before TZD treatment) when assessed either 24 h or 3 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.