Protective Role of Peroxisome Proliferator–Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture

Shimada, Kenji; Furukawa, Hajime; Wada, Kodai; Korai, Masaaki; Wei, Yuan; Tada, Yasuyuki; Kuwabara, Atsushi; Shikata, Fumiaki; Kitazato, Keiko T.; Saijo, Nagahiro; Lawton, Michael T.; Hashimoto, Tomoki

doi:10.1161/strokeaha.114.007722

Cited by 70 publications

(75 citation statements)

References 35 publications

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“…It is reported recently that PPARγ protects against the development of aneurismal rupture. 22 And PPARγ agonists (just as rosiglitazone and pioglitazone) are used to treat clinical diabetes mellitus and to study effects mainly in ischemic stroke for many years. Although there is more widespread distribution and content of PPARβ/δ in the central nervous system than other 2 subtypes-PPARα and PPARγ, 23 little is known about the exact function of PPARβ/δ in central nervous system disease.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Teng

Jiang

et al. 2016

Stroke

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S ubarachnoid hemorrhage (SAH) is a devastating disease with high mortality and disability. Traditionally, cerebral vasospasm, which develops in large cerebral arteries 3 to 7 days after SAH, was considered the most crucial cause of serious consequences after SAH. However, recent studies have shown that there is little advance in improving the outcome of SAH by prevention of vasospasm. It is reported that 12% of SAH patients die before receiving medical attention and 33% within 48 hours of SAH and 50% survivors havepermanent disability.1 The primary determinant of poor outcome in SAH patients was proposed to be early brain injury (EBI).2,3 EBI was described as the immediate injury of the brain after SAH, including elevation of intracranial pressure, disruption of bloodbrain barrier (BBB), neuronal cell death, brain edema, and other pathophysiologic changes. 4,5 Several recent studies have indicated apoptosis might play an important role in the pathogenesis of EBI after SAH. 6Background and Purpose-Early brain injury is proposed to be the primary cause of the poor outcome after subarachnoid hemorrhage (SAH), which is closely related to the neural apoptosis. To date, the relationship between peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and nuclear factor-κB/matrix metalloproteinase-9 (NF-κB/MMP-9) pathway, both of which are closely related to apoptotic effects, has been poorly studied in SAH. The present study was undertaken to evaluate the effects of PPARβ/δ on early brain injury and NF-κB/MMP-9 pathway after SAH in rats. Methods-SAH model was established by injecting nonheparinized autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Adenoviruses or small interfering RNAs were injected into the right lateral cerebral ventricle to, respectively, up-or downregulate PPARβ/δ expression before SAH. All animals were assessed with a neurological score and then killed at 24 hours after SAH surgery. The indexes of brain water content, blood-brain barrier permeability, and apoptosis were used to detect brain injury. The expression of PPARβ/δ, NF-κB, and MMP-9 were measured by immunohistochemistry, gelatin zymography, and Western Blot methods, respectively. In addition, GW0742, a specific agonist of PPARβ/δ, was used to treat SAH in rats, the effects of which were evaluated by neurological scoring and Evans blue extravasation. Results-Overexpression of PPARβ/δ by adenoviruses treatment significantly ameliorated brain injury with improvement in neurological deficits, brain edema, blood-brain barrier impairment, and neural cell apoptosis at 24 hours after SAH in rats, whereas downregulation of PPARβ/δ by small interfering RNAs administration resulted in the reverse effects of the above. The expression levels of NF-κB and MMP-9 were markedly downregulated when PPARβ/δ increased after PPARβ/δ adenovirus transfection and upregulated when PPARβ/δ decreased by PPARβ/δ small interfering RNAs treatment. Moreover, GW0742 improved neurological deficits and reduced Evans blue extravasation ...

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Teng

Jiang

et al. 2016

Stroke

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“…Mice were injected with these treatments immediately after collagenase injection and then once daily until euthanasia. The delivery route and dosing regimens were based on previous work (Allahtavakoli et al, 2006; Burton et al, 2008; Cuartero et al, 2013; Hyong et al, 2008; Luo et al, 2006; Shimada et al, 2015; Zhao et al, 2009) and our own preliminary tests.…”

Section: Methodsmentioning

confidence: 99%

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Chang

Wan

et al. 2017

Neurobiology of Disease

113

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Microglia/macrophages (MMΦ) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMΦ polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMΦ dynamics after ICH in mice and evaluated the relevance of MMΦ polarity to hematoma resolution. MMΦ accumulated within the hematoma territory until at least 14 days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1–1.5 h after ICH and specifically presented a “protective” alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMΦ classic activation dominated at the chronic stage of ICH. We enhanced MMΦ alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMΦ alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMΦ respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMΦ aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMΦ phagocytosis and hematoma clearance in ICH.

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“…Recent studies have revealed that chronic inflammatory responses underlie IA growth 3, 4. In fact, several anti‐inflammatory agents inhibit aneurysms in rodent models,5, 6 yet no clinical trial has conclusively demonstrated the effectiveness of these reagents in humans.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.Methods and Results IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

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Protective Role of Peroxisome Proliferator–Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture

Cited by 70 publications

References 35 publications

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

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