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PPARs: A Potential Target for a Disease-Modifying Strategy in Stroke
Abstract and Figures
Stroke is one of the major causes of mortality and disability in adults in industrialized countries. Despite numerous preclinical studies and clinical trials in the field of cerebral ischemia, no pharmacological agent has been validated in the treatment of acute ischemic, except thrombolysis. Cerebral ischemia is not only a neuronal disease but it affects the entire neurovascular unit. The therapeutic strategy in stroke should be more global and combine preventive approaches, acute phase treatment and long-term care to improve recovery and prevent or treat affective and cognitive post-stroke consequences. There is an imperative need to develop disease-modifying drugs, which should be able to induce neuroprotection, to serve as adjuvants for thrombolysis by decreasing the hemorrhagic risk and to limit the long-term post-stroke consequences. This review presents the potential effects of Peroxisome Proliferator-Activated Receptors (PPARs) and of their agonists in stroke. We focus on each PPAR receptor and detail their implication in stroke. PPARs are nuclear receptors, acting as ligand-dependent transcription factors. They are expressed in the neurovascular unit that suggests that PPARs could play a role in stroke. Indeed, it has been shown that they are able to interfere with pathways implicated in the pathophysiology of stroke. They could be an answer to this disease-modifying drug concept, being able to act on the different phases of ischemia.
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... Genistein eliminates Aβ-induced inflammation in cultivated astrocytes. [23][24][25][26][27] Genistein stops the accumulation of Aβ and behavioral deficits through interactions with PPARγ in a mouse with AD. 28 Several cognitive features (recognition memory, hippocampal learning, odor discrimination, and implicit memory), as well as a decrease in the number and region of Aβ plaques, have been enhanced by genistein therapy. 29 ...
In specific populations, soy products have been a part of their diet for many centuries. Soybeans are known to be beneficial mostly because of being rich sources of isoflavones. Various studies showed that Soy isoflavones such as daidzein and genistein have positive effects on gastrointestinal health, cancer prevention, and health promotion in postmenopausal women. In recent years, many studies focused on the neuroprotective effects of soy isoflavones in animal models and humans. This review includes the latest literature on the effects of soy isoflavones in various neurological disorders. In conclusion, soy isoflavones have neuroprotective, anti-inflammatory, and anti-oxidant effects and can be used to prevent stroke, improve memory and cognitive function, reduction of Parkinson’s disease symptoms, and also as a therapeutic agent in multiple sclerosis.
... Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily, acting as a ligand-activated transcription factor [4]. Administration of PPAR-γ agonists has been shown to protect against cerebral ischemia through multiple mechanisms, such as by inhibition of post-ischemic oxidative stress [5,6], apoptosis [5], and ischemia-induced in ammation [6][7][8][9]. ...
Background
Rosiglitazone (RSG) is a widely used antidiabetic drug which activates peroxisome proliferator-activated receptor-γ. Recent work have shown that RSG can up-regulate caveolin-1 levels and ameliorate both chronic and acute brain injury. However, whether rosiglitazone can ameliorate ischemic injury in the brain via a caveolin-1-dependent pathway remains unknown.
Methods
Adult male sprague-dawley rats were randomly divided into sham operation group, model group, rosiglitazone group and rosiglitazone + daidzein group. The rat models of middle cerebral artery occlusion (MCAO) was established using the suture method, with ischemia for 2 hours and reperfusion for 22 hours. Neurological deficits were evaluated by the methods of Longa’s standard scoring. Cerebral infarction volume was observed by staining with 2, 3, 5-triphenyltetrazolium chloride. Evans blue content reflects BBB permeability. The expressions of caveolin-1, matrix metalloproteinase-9(MMP-9) and occludin were detected by immunofluorescent staining and western blot.
Results
In this study, we found that the expression of caveolin-1 was increased in a rat model of stroke, and treatment with RSG significantly increased the levels of caveolin-1, reduced the release of MMP-9, and increased the expression of occludin. On the other hand, a caveolin-1 inhibitor daidzein canceled the protective roles of RSG in the MCAO model.
Conclusions
These data unveil that RSG might protect blood-brain barrier integrity by down-regulating the levels of MMP-9 via a caveolin-1-dependent pathway.
... Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily, acting as a ligand-activated transcription factor [4]. Administration of PPAR-γ agonists has been shown to protect against cerebral ischemia through multiple mechanisms, such as by inhibition of post-ischemic oxidative stress [5,6], apoptosis [5], and ischemia-induced in ammation [6][7][8][9]. ...
Background: Rosiglitazone (RSG) is a widely used antidiabetic drug which activates peroxisome proliferator-activated receptor-γ. Recent work have shown that RSG can up-regulate caveolin-1 levels and ameliorate both chronic and acute brain injury. However, whether rosiglitazone can ameliorate ischemic injury in the brain via a caveolin-1-dependent pathway remains unknown.
Methods: Adult male sprague-dawley rats were randomly divided into sham operation group, model group, rosiglitazone group and rosiglitazone+daidzein group. The rat models of middle cerebral artery occlusion (MCAO) was established using the suture method, with ischemia for 2 hours and reperfusion for 22 hours. Neurological deficits were evaluated by the methods of Longa’s standard scoring. Cerebral infarction volume was observed by staining with 2, 3, 5-triphenyltetrazolium chloride. Evans blue content reflects BBB permeability. The expressions of caveolin-1, matrix metalloproteinase-9(MMP-9) and occludin were detected by immunofluorescent staining and western blot.
Results: In this study, we found that the expression of caveolin-1 was increased in a rat model of stroke, and treatment with RSG significantly increased the levels of caveolin-1, reduced the release of MMP-9, and increased the expression of occludin. On the other hand, a caveolin-1 inhibitor daidzein canceled the protective roles of RSG in the MCAO model.
Conclusions: These data unveil that RSG might protect blood-brain barrier integrity by down-regulating the levels of MMP-9 via a caveolin-1-dependent pathway.
... Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily, acting as a ligand-activated transcription factor [4]. Administration of PPAR-γ agonists has been shown to protect against cerebral ischemia through multiple mechanisms, such as by inhibition of post-ischemic oxidative stress [5,6], apoptosis [5], and ischemia-induced in ammation [6][7][8][9]. ...
Background: Rosiglitazone (RSG) is a widely used antidiabetic drug which activates peroxisome proliferator-activated receptor-γ. Recent work have shown that RSG can up-regulate caveolin-1 levels and ameliorate both chronic and acute brain injury. However, whether rosiglitazone can ameliorate ischemic injury in the brain via a caveolin-1-dependent pathway remains unknown.
Methods: Adult male sprague-dawley rats were randomly divided into sham operation group, model group, rosiglitazone group and rosiglitazone+daidzein group. The rat models of middle cerebral artery occlusion (MCAO) was established using the suture method, with ischemia for 2 hours and reperfusion for 22 hours. Neurological deficits were evaluated by the methods of Longa’s standard scoring. Cerebral infarction volume was observed by staining with 2, 3, 5-triphenyltetrazolium chloride. Evans blue content reflects BBB permeability. The expressions of caveolin-1, matrix metalloproteinase-9(MMP-9) and occludin were detected by immunofluorescent staining and western blot.
Results: In this study, we found that the expression of caveolin-1 was increased in a rat model of stroke, and treatment with RSG significantly increased the levels of caveolin-1, reduced the release of MMP-9, and increased the expression of occludin. On the other hand, a caveolin-1 inhibitor daidzein canceled the protective roles of RSG in the MCAO model.
Conclusions: These data unveil that RSG might protect blood-brain barrier integrity by down-regulating the levels of MMP-9 via a caveolin-1-dependent pathway.
... Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily, acting as a ligand-activated transcription factor [4]. Administration of PPAR-γ agonists has been shown to protect against cerebral ischemia through multiple mechanisms, such as by inhibition of post-ischemic oxidative stress [5,6], apoptosis [5], and ischemia-induced in ammation [6][7][8][9]. ...
Background: Rosiglitazone (RSG) is a widely used antidiabetic drug which activates peroxisome proliferator-activated receptor-γ. Recent work have shown that RSG can up-regulate caveolin-1 levels and ameliorate both chronic and acute brain injury. However, whether rosiglitazone can ameliorate ischemic injury in the brain via a caveolin-1-dependent pathway remains unknown.
Methods: Adult male sprague-dawley rats were randomly divided into sham operation group, model group, rosiglitazone group and rosiglitazone+daidzein group. The rat models of middle cerebral artery occlusion (MCAO) was established using the suture method, with ischemia for 2 hours and reperfusion for 22 hours. Neurological deficits were evaluated by the methods of Longa’s standard scoring. Cerebral infarction volume was observed by staining with 2, 3, 5-triphenyltetrazolium chloride. Evans blue content reflects BBB permeability. The expressions of caveolin-1, matrix metalloproteinase-9(MMP-9) and occludin were detected by immunofluorescent staining and western blot.
Results: In this study, we found that the expression of caveolin-1 was increased in a rat model of stroke, and treatment with RSG significantly increased the levels of caveolin-1, reduced the release of MMP-9, and increased the expression of occludin. On the other hand, a caveolin-1 inhibitor daidzein canceled the protective roles of RSG in the MCAO model.
Conclusions: These data unveil that RSG might protect blood-brain barrier integrity by down-regulating the levels of MMP-9 via a caveolin-1-dependent pathway.
... Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily, acting as a ligand-activated transcription factor [4]. Administration of PPAR-γ agonists has been shown to protect against cerebral ischemia through multiple mechanisms, such as by inhibition of post-ischemic oxidative stress [5,6], apoptosis [5], and ischemia-induced in ammation [6][7][8][9]. ...
Background
Rosiglitazone (RSG) is a widely used antidiabetic drug which activates peroxisome proliferator-activated receptor-γ. Recent work have shown that RSG can up-regulate caveolin-1 levels and ameliorate both chronic and acute brain injury. However, whether rosiglitazone can ameliorate ischemic injury in the brain via a caveolin-1-dependent pathway remains unknown.
Methods
Adult male sprague-dawley rats were randomly divided into sham operation group, model group, rosiglitazone group and rosiglitazone + daidzein group. The rat models of middle cerebral artery occlusion (MCAO) was established using the suture method, with ischemia for 2 hours and reperfusion for 22 hours. Neurological deficits were evaluated by the methods of Longa’s standard scoring. Cerebral infarction volume was observed by staining with 2, 3, 5-triphenyltetrazolium chloride. Evans blue content reflects BBB permeability. The expressions of caveolin-1, matrix metalloproteinase-9(MMP-9) and occludin were detected by immunofluorescent staining and western blot.
Results
In this study, we found that the expression of caveolin-1 was increased in a rat model of stroke, and treatment with RSG significantly increased the levels of caveolin-1, reduced the release of MMP-9, and increased the expression of occludin. On the other hand, a caveolin-1 inhibitor daidzein canceled the protective roles of RSG in the MCAO model.
Conclusions
These data unveil that RSG might protect blood-brain barrier integrity by down-regulating the levels of MMP-9 via a caveolin-1-dependent pathway.
The brain is not the central organ, isolated in its skull that we usually imagine. It is connected to many other organs including the liver. Brain‐liver relationships result from metabolic, hormonal, immunological or inflammatory pathways.
Traumatic brain injury (TBI) is the major cause of high mortality and disability rates worldwide. Pioglitazone is an activator of peroxisome proliferator-activated receptor-gamma (PPARγ) that can reduce inflammation following TBI. Clinically, neuroinflammation after TBI lacks effective treatment. Although there are many studies on PPARγ in TBI animals, only few could be converted into clinical, since TBI mechanisms in humans and animals are not completely consistent. The present study, provided a potential theoretical basis and therapeutic target for neuroinflammation treatment after TBI. First, we detected interleukin-6 (IL-6), nitric oxide (NO) and Caspase-3 in TBI clinical specimens, confirming a presence of a high expression of inflammatory factors. Western blot (WB), quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to detect PPARγ, IL-6, and p-NF-κB to identify the mechanisms of neuroinflammation. Then, in the rat TBI model, neurobehavioral and cerebral edema levels were investigated after intervention with pioglitazone (PPARγ activator) or T0070907 (PPARγ inhibitor), and PPARγ, IL-6 and p-NF-κB were detected again by qRT-PCR, WB and immunofluorescence (IF). The obtained results revealed that: 1) increased expression of IL-6, NO and Caspase-3 in serum and cerebrospinal fluid in patients after TBI, and decreased PPARγ in brain tissue; 2) pioglitazone could improve neurobehavioral and reduce brain edema in rats after TBI; 3) the protective effect of pioglitazone was achieved by activating PPARγ and reducing NF-κB and IL-6. The neuroprotective effect of pioglitazone on TBI was mediated through the PPARγ/NF-κB/IL-6 pathway.
Angiogenesis of brain microvascular endothelial cells (BMECs) is required in the functional restoration of brain injury, such as traumatic brain injury (TBI) and ischemic stroke. Fibroblast growth factor 21 (FGF21) is an angiogenic molecule that functions through the formation of the FGF21/FGFR1/β-klotho complex but does not cause carcinogenic events. The current study was to determine whether recombinant human FGF21 (rhFGF21) could promote angiogenesis and scratch wound healing of human brain microvascular endothelial cells (HBMECs) and the possible underlying mechanism. rhFGF21 promoted angiogenesis and migration of HBMECs. The FGFR1 inhibitor PD173074 was applied to demonstrate that rhFGF21 functions through the formation of FGF21/FGFR1/β-klotho complexes. In addition, the specific PPARγ inhibitor GW9662 and PPARγ activator rosiglitazone were applied to determine that the role of rhFGF21 in increasing angiogenesis is through the PPARγ pathway. In addition, we revealed that the effect of rhFGF21 acts partially through upregulating eNOS expression. In conclusion, our study provides novel evidence that rhFGF21 can enhance the angiogenesis and migration of HBMECs through the formation of the FGF21/FGFR1/β-klotho complex via PPARγ activation and eNOS upregulation, indicating that FGF21 is a potential therapeutic angiogenic agent for the treatment of human brain injury. Keywords: Angiogenesis, Wound healing, FGF21, FGF21/FGFR1/β-klotho complex, PPARγ
Cytokines are pivotal mediators of the immune response, and their coordinated expression protects host tissue from excessive damage and oxidant stress. Nevertheless, the development of lung pathology, including asthma, chronic obstructive pulmonary disease, and ozone-induced lung injury, is associated with oxidant stress; as evidence, there is a significant increase in levels of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) in the genome. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NF-κB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitments of inflammatory cells. Hence, defective OGG1 will modulate the coordination between innate and adaptive immunity through excessive oxidant stress and cytokine dysregulation. Both oxidant stress and cytokine dysregulation constitute key elements of oncogenesis by KRAS, which is mechanistically coupled to OGG1. Thus, analysis of the mechanism by which OGG1 modulates gene expression helps discern between beneficial and detrimental effects of oxidant stress, exposes a missing functional link as a marker, and yields a novel target for lung cancer.
purpose. The peroxisome proliferator-activated receptor-γ (PPAR-γ) is the target of the insulin sensitizing thiazolidinediones (TZDs), a class of drugs used in the treatment of type 2 diabetes mellitus. Glaucoma and other retinal disorders are some of the major complications in diabetes. In the present study, the role that PPAR-γ ligands play in protecting retinal ganglion cells (RGC-5) against glutamate insult was explored.
methods. Transformed rat RGC (RGC-5 cells) and two PPAR-γ agonists, 15-deoxy-d 12,14-prostaglandin J2 (15d-PGJ2) and troglitazone were used. RGC-5 cells were incubated with either of the PPAR-γ ligands and were exposed to either l-glutamic acid or buthionine sulfoximine (BSO). Cell viability was determined with the neutral red dye uptake assay. Levels of PPAR-γ receptor proteins were monitored by immunoblot analysis.
results. Glutamate treatment resulted in RGC-5 cell death, and both 15d-PGJ2 and troglitazone protected the RGC-5 cells from glutamate cytotoxicity. The neuroprotective concentrations of both compounds ranged from approximately 1 to 5 μM. Troglitazone further protected against BSO toxicity, whereas 15d-PGJ2 did not. Glutamate treatment appears to exert its cytotoxicity through oxidative damage, because pretreatment of RGC-5 cells with the antioxidants N-acetyl cysteine (NAC) and thiourea resulted in the reversal of glutamate cytotoxicity. Furthermore, the glutamate effect was not reversed by pretreatment with MK801 or dl-threo-betabenzyloxyaspartate (dl-TBOA), suggesting that glutamate cytotoxicity is not mediated through the NMDA receptor and/or glutamate transporter, respectively. Levels of PPAR-γ receptor protein did not show any appreciable change in response to glutamate exposure, with or without 15d-PGJ2 or troglitazone.
conclusions. Two PPAR-γ ligands, 15d-PGJ2 and troglitazone, protect RGC-5, an established transformed rat retinal ganglion cell line, against glutamate cytotoxicity. The neuroprotective effects of the two compounds appear to be mediated through an antioxidant rather than a PPAR-γ–dependent pathway. These results suggest that PPAR-γ agonists, in addition to improving insulin sensitivity, may also provide a valuable antioxidant benefit that could prove valuable in targeting ocular complications including glaucoma.
Objective— Peroxisome proliferator-activated receptor γ (PPARγ) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPARγ ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall.
Methods and Results— The PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPARγ was transcriptionally functional. Treatment with 15d-PGJ2 or ciglitazone significantly increased release of ·NO from PAECs or human aortic endothelial cells and augmented calcium ionophore–induced ·NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in ·NO release caused by treatment with 15d-PGJ2 occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor α-amanitin. Overexpression of PPARγ or treatment with 9-cis retinoic acid also enhanced PAEC ·NO release. Neither 15d-PGJ2 nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ2, but not ciglitazone, decreased eNOS protein.
Conclusions— Taken together, these findings demonstrate that PPARγ ligands stimulate ·NO release from endothelial cells derived from multiple vascular sites, through a transcriptional mechanism unrelated to eNOS expression.
Although considerable research has shown a role for peroxisome proliferator-activated receptors (PPAR) in adipose differentiation and in the regulation of inflammation, little is known about its possible functions in neurons. We investigated the role of PPAR gamma in primary cultures of cortical neurons and human neuroblastoma SH-SY5Y cells. Incubation of cortical neurons with the specific PPAR gamma ligand 15-Deoxy-Delta (12,14)-prostaglandin J(2) (15d-PGJ(2)) induced morphological changes including neurite degeneration and nuclear condensation that were consistent with neurons dying by apoptosis. The morphological changes associated with incubation of cortical neurons with 15d-PGJ(2) were prevented following pretreatment of neurons with the general caspase inhibitor, Z-VAD. These results highlight a novel role for PPAR gamma in neurons and suggest that unwarranted activation of PPAR gamma may contribute to the neuronal apoptosis associated with certain neurodegenerative disorders including Alzheimer's disease (AD). NeuroReport 12:839-843 (C) 2001 Lippincott Williams & Wilkins.
We examined the effects of a variety of ligands/activators of the peroxisome proliferator-activated receptor (PPAR) on the expression of the superoxide scavenger enzyme, Cu2+,Zn2+-superoxide dismutase (CuZn-SOD), and the superoxide generating enzyme nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase in primary cultures of human umbilical vein endothelial cells (HUVEC) and human aorta endothelial cells (HAEC). Our data show that 3 types of PPARs, PPARα, PPARβ/δ/Nuc1, and PPARγ are expressed in endothelial cells. Bezafibrate, which is a ligand/activator for PPARα, increased the CuZn-SOD gene expression and protein levels in endothelial cells. Troglitazone and pioglitazone, which are ligands/activators for PPARγ, also induced PPARα gene and protein expression and increased CuZn-SOD gene expression and protein levels in addition to increasing PPARγ gene and protein expression in endothelial cells. Moreover, with treatment of monounsaturated and polyunsaturated fatty acids (PUFA), the CuZn-SOD mRNA levels were positively correlated with PPARα mRNA levels (r = .872, P < .0001) in primary endothelial cells. In addition, the phorbol myristate acetate (PMA)-stimulated or PMA-nonstimulated 22-kd a-subunit (p22phox) mRNA levels and 47-kd a-subunit (p47phox) protein levels in NADPH oxidase were decreased by treatment with PPARα and PPARγ ligands/activators. These results suggest that PPARα and PPARγ gene and protein expression in endothelial cells may play a physiologic role as radical scavengers, although the details of these mechanisms remain to be established.
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors which belong to the nuclear receptor family. We examined whether PPARα agonists and resveratrol, a polyphenol contained in grapes, protect the brain against ischemia. To investigate whether resveratrol activates PPARs, we performed a cell-based transfection activity assay using luciferase reporter plasmid. PPARα and PPARγ were activated by resveratrol in primary cortical cultures and vascular endothelial cells. Resveratrol (20 mg/kg, 3 days) reduced infarct volume by 36% at 24 h after middle cerebral artery occlusion in wild-type mice. The PPARα agonists fenofibrate (30 mg/kg, 3 days) and Wy-14643 (30 mg/kg, days) exerted similar brain protection. However, resveratrol and fenofibrate failed to protect the brain in PPARα knockout mice. The data indicate that PPARα agonists protect the brain through PPARα.