Peroxisome proliferator-activated receptor-γ agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents

Authors

  • Kudret Tureyen,

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
    2. Department of Neurosurgery, University of Suleyman Demirel, Isparta, Turkey
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    • These authors contributed equally to this work.

  • Ramya Kapadia,

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
    2. Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA
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    • These authors contributed equally to this work.

  • Kellie K. Bowen,

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
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  • Irawan Satriotomo,

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
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  • Jin Liang,

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
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  • Douglas L. Feinstein,

    1. Department of Anesthesiology, University of Illinois-Chicago, Chicago, Illinois, USA
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  • Raghu Vemuganti

    1. Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
    2. Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, USA
    3. Cardiovascular Research Center, University of Wisconsin, Madison, Wisconsin, USA
    4. Regenerative Medicine Program, University of Wisconsin, Madison, Wisconsin, USA
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  • [Correction added after online publication 19 January 2007: in the author running head, R. Tureyen et al. was corrected to K. Tureyen et al.]

Address correspondence and reprint requests to Raghu Vemuganti, PhD, Assistant Professor, Department of Neurological Surgery, University of Wisconsin, K4/8 (Mail stop code CSC-8660), 600 Highland Ave, Madison, WI 53792, USA. E-mail: vemugant@neurosurg.wisc.edu

Abstract

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid × receptor agonist 9-cis-retinoic acid, but was prevented by PPARγ antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1β, interleukin-6, macrophage inflammatory protein-1α, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-β and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARγ activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.

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