Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: Effects of the PPAR-α agonist WY14643

Collino, Massimo; Aragno, Manuela; Mastrocola, Raffaella; Benetti, Elisa; Gallicchio, Margherita; Dianzani, Chiara; Danni, Oliviero; Thiemermann, Christoph; Fantozzi, Roberto

doi:10.1016/j.freeradbiomed.2006.04.030

Cited by 145 publications

(111 citation statements)

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“…In addition, it appears that pioglitazone also functions as a partial PPARalpha agonist, whereas rosiglitazone functions as a pure PPAR-gamma agonist (47). PPARalpha activation is also known to induce neuroprotection after focal ischemia (26,122). The fact that pioglitazone, which has a lower affinity for PPAR-gamma activation, is effective at much lower concentrations than a pure PPAR-gamma agonist such as rosiglitazone, indicates that other factors must be involved in determining the efficacy individual TZDs.…”

Section: Ligand Efficacy Of Ppar Agonists Rosiglitazone and Pioglitamentioning

confidence: 99%

“…Recent studies have shown that transcription factors like interferon regulatory factor (IRF)-1, signal transducer and activator of transcription (STAT)-3, nuclear factor (NF)-kappaB, CCAAT/ enhancer binding protein (C/EBP)-beta and early growth response (EGR)-1 promote inflammatory gene expression and thus precipitates severe neuronal damage (60,69,123,128,129). On the other hand, the activation of transcription factors like nuclear factor-E2 related factor (Nrf)-2, peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, cAMP response element-binding protein (CREB) and hypoxia-inducible factor (HIF)-1 have been suggested to be neuroprotective since they curtail oxidative stress and inflammatory gene expression (33,52,107,114,122). As the transcription of inflammatory genes is the first step of any inflammatory cascade, therapies that target the pro-inflammatory transcriptional events will potentially curtail inflammation at the very beginning of the signalling process.…”

Section: Role Of Transcription Factors In Post-ischemic Inflammationmentioning

confidence: 99%

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Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

374

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Section: Ligand Efficacy Of Ppar Agonists Rosiglitazone and Pioglitamentioning

confidence: 99%

Section: Role Of Transcription Factors In Post-ischemic Inflammationmentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

374

246

View full text Add to dashboard Cite

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“…Beyond metabolic effects, PPARα activation also induces antiinflammatory and antioxidant effects in different organs. Several studies indicated that Wy14643 protected organs such as heart, kidney and brain against ischemiareperfusion injury [9][10][11][12] . PPAR-α represses the expression of inflammatory-response genes via a mechanism termed ligand-dependent transrepression [13] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Wy14643 on hepatic ischemia reperfusion injury in rats

Xu¹,

Li²,

Hu³

et al. 2008

WJG

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“…The experimental protocol was performed as described previously (13). Briefly, rats were anesthetized through injection of 30 mg/kg Zoletil 100 i.p.…”

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confidence: 99%

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

et al. 2009

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OBJECTIVE-There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3␤ (GSK-3␤). Here, we investigate the role of GSK-3␤ inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes. RESEARCH DESIGN AND METHODS-Ratswith streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2-12 IU/kg i.v.) or the selective GSK-3␤ inhibitor TDZD-8 (0.2-3 mg/kg i.v.) was administered during reperfusion.RESULTS-Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3␤ in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drugtreated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-B was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-␣; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression.CONCLUSIONS-Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3␤ contributes to the protective effect of insulin independently of any effects on blood glucose. Diabetes 58:235-242, 2009 E pidemiological studies have shown that diabetes is a leading risk factor for ischemic cerebrovascular diseases (1). Animal and human studies demonstrate that insulin reduces brain damage evoked by ischemia/reperfusion (I/R) injury (2,3). Glycemic control by insulin may be involved in this protective effect, but the molecular mechanisms underlying the protective effects of insulin are debated and still poorly understood (4). One important pharmacological effect of insulin is its ability to inhibit the activity of the glycogen synthase kinase (GSK)-3, a serine/threonine kinase that was originally identified for its key role in glucose metabolism (5). More recently, GSK-3 has emerged as a key regulatory switch in the modulation of neurodegeneration and inflammation (6,7). There are two mammalian isoforms of GSK-3: GSK-3␣ and GSK-3␤. GSK-3␤ is highly expressed in the central nervous system (8). Unlike most kinases, GSK-3␤ is constitutively active in cells and can be inactivated by phosphorylation at Ser9 (9). Binding of insulin to its receptor activates phosphatidylinositol 3-kinase, leading to the subsequent activation of protein kinase B/Akt, and the inactivation of GSK-3␤ by phosphorylation on the regulatory Ser-9. This contributes to the insulin-induce...

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Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: Effects of the PPAR-α agonist WY14643

Cited by 145 publications

References 55 publications

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Effects of Wy14643 on hepatic ischemia reperfusion injury in rats

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

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