PPAR-γ: therapeutic target for ischemic stroke

Čulman, Juraj; Zhao, Yi; Gohlke, Peter; Herdegen, Thomas

doi:10.1016/j.tips.2007.03.004

Cited by 147 publications

(121 citation statements)

References 58 publications

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“…174 DNA binding is restored by PPAR␥ ligands, 170,174,175 and these agents have been shown to reduce ischemic injury in rodent stroke models. 176 Treatment with PPAR␥ ligands reduces microglia and macrophage activation and migration to the periinfarct regions, 177,178 attenuates the expression of ICAM-1, MMP-9, IL-1␤, COX-2, TNF␣, and iNOS, and suppresses production of reactive oxygen species. 177,179 …”

Section: Ppar␥mentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Section: Ppar␥mentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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“…Growing evidence indicates that PPARγ agonists efficiently display neuroprotective properties in response to harmful insults, particularly neuroinflammation. Activation of PPARγ by troglitazone and pioglitazone reduces infarct volume by improving neurological function following middle cerebral artery occlusion in rats (Corona & Duchen, 2016; Culman, Zhao, Gohlke & Herdegen, 2007). Also, PPARγ activation by rosiglitazone imparts antidepressant‐ and anxiolytic‐like effects (Guo et al., 2017).…”

Section: Introductionmentioning

confidence: 99%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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SummaryMicroglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.

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“…The activation of PPARγ by T33 at the beginning of OGD did not lead to a higher level of activity of PPARγ after reperfusion, which could be attributed to mitigated stress by the treatment of T33. Moreover, previous studies have suggested that the activation of PPARγ promotes the repression of the exaggerated expression of inflammatory mediators that occurs in response to transient cerebral ischemia [12,38] . These actions of PPARγ could be mediated, at least in part, by inhibiting the I-κBα/NF-κB pathway, since I-κBα is a PPARγ target gene [39] .…”

Section: Discussionmentioning

confidence: 99%

“…Most of the anti-inflammatory activities of PPARγ have been suggested to arise through the inhibition of NF-κB, a transcription factor controlling the expression of multiple inflammatory genes during ischemia [10] . Moreover, emerging evidence implies that PPARγ activation is protective against brain damage after stroke, and PPARγ deficiency promotes brain damage after stroke [12][13][14] . Synthesized PPARγ agonists, including the wellknown thiazolidinediones (TZDs), exhibit potent neuroprotective effects in stroke models mainly by blocking the production of inflammatory mediators [15,16] .…”

Section: Introductionmentioning

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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PPAR-γ: therapeutic target for ischemic stroke

Cited by 147 publications

References 58 publications

Microglial Activation in Stroke: Therapeutic Targets

Microglial Activation in Stroke: Therapeutic Targets

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

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

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