Modulation of the oxidative stress and inflammatory response by PPAR-γ agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion

Collino, Massimo; Aragno, Manuela; Mastrocola, Raffaella; Gallicchio, Margherita; Rosa, Arianna Carolina; Dianzani, Chiara; Danni, Oliviero; Thiemermann, Christoph; Fantozzi, Roberto

doi:10.1016/j.ejphar.2005.11.049

Cited by 272 publications

(195 citation statements)

References 74 publications

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“…Although the anti-inflammatory action of PPARg is known to have a major role in neuroprotection, other beneficial effects of PPARg and its agonists, such as reducing oxidative stress and preventing apoptosis after ischemia, have been reported. 24,25 Our study demonstrates a mechanism by which rosiglitazone can block phosphorylation of JNK and hence reduce cell death. In our present study, we examined the SAPK signaling pathway underlying the effect of rosiglitazone and activation of PPARg.…”

Section: Discussionmentioning

confidence: 71%

“…Our data are in agreement with a previous study that showed that rosiglitazone prevented phosphorylation of p38 MAPK induced by global ischemia. 24 The relationship between high-reactive oxygen species and activation of downstream signaling cascades has been clearly shown. Collino et al 24 have also suggested the ability of rosiglitazone to reduce oxidative stress via its action on signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…24 The relationship between high-reactive oxygen species and activation of downstream signaling cascades has been clearly shown. Collino et al 24 have also suggested the ability of rosiglitazone to reduce oxidative stress via its action on signaling pathways. Activation of either JNK or p38 MAPK is well documented in cerebral ischemia models.…”

Section: Discussionmentioning

confidence: 99%

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Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

Okami

Narasimhan

Yoshioka

et al. 2012

J Cereb Blood Flow Metab

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Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-g (PPARg) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARg antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

Okami

Narasimhan

Yoshioka

et al. 2012

J Cereb Blood Flow Metab

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“…First, the possibility cannot be ruled out that the brain utilises more of a fuel other than glucose, such as lactate of peripheral origin [37]. Second, pioglitazone treatment may be protective by limiting the highest rates of regional glucose oxidative metabolism and the concomitant oxidative stress [14,32,38,39], in association with the benefits derived from the attenuation of inflammation [5]. Finally, pioglitazone can induce the expression of proteins related to the stress response [40] and mitochondrial membrane hyperpolarisation that can safeguard the cells against an excessive metabolic rate [9].…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

2006

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Aims/hypothesis Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. Materials and methods The regional pattern of CGU was measured with the 2-deoxy [ 14 C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor β1 (TGFβ1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months.Results Measurement of CGU in 27 brain regions confirmed that TGFβ1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFβ1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFβ1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. Conclusions/interpretation In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.

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“…Because PPARγ agonists are capable of modulating inflammatory responses by reducing the activation of p38 and NF-κB in activated glial cells [50] , we hypothesized that PPARγ agonizing might contribute to the anti-inflammatory activity of T33 in an in vivo MCAO ischemic model. Since post-ischemic brain inflammation contributes largely to the formation of brain infarction, the neuroprotective effect of T33 was further evaluated.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Aim: To examine the neuroprotective effects of T33, a peroxisome proliferator-activated receptor gamma/alpha (PPARγ/α) agonist, in acute ischemic models in vitro and in vivo. Methods: Primary astrocytes subjected to oxygen-glucose deprivation/reperfusion (O/R) and BV-2 cells subjected to hypoxia were used as a model simulating the ischemic core and penumbra, respectively. The mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using qPCR. The levels of TNF-α secreted by BV-2 cells were measured using ELISA. Protein levels of cyclooxygenase-2 (COX-2), p65, phosphorylated I-κBα/I-κBα, phosphorylated I-κB kinase (pIKK), phosphorylated eukaryote initiation factor 2α (p-eIF-2α)/eIF-2α and p-p38/p38 were detected using Western blot. PPARγ activity was measured using EMSA. The neuroprotection in vivo was examined in rat middle cerebral artery occlusion (MCAO) model with neurological scoring and TTC staining. Results: Addition of T33 (0.5 µmol/L) increased the level of I-κBα protein in primary astrocytes subjected to O/R, which was due to promoting protein synthesis without affecting degradation. In primary astrocytes subjected to O/R, addition of T33 amplified I-κBα gene transcription and mRNA translation, thus suppressing the nuclear factor-kappa B (NF-κB) pathway and reducing inflammatory mediators (TNF-α, IL-1β, and COX-2). In BV-2 cells subjected to hypoxia, T33 (0.5 µmol/L) reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARγ antagonist GW9662 (30 µmol/L). T33 (2 mg/kg, ip) attenuated MCAO-induced inflammatory responses and brain infarction, which was antagonized by pre-administered GW9662 (4 mg/kg, ip). Conclusion: T33 exerted anti-inflammatory effects in the ischemic core and penumbra via PPARγ activation, which contributed to its neuroprotective action.

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Modulation of the oxidative stress and inflammatory response by PPAR-γ agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion

Cited by 272 publications

References 74 publications

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

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

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