Peroxisome Proliferator-Activated Receptor-α Activation as a Mechanism of Preventive Neuroprotection Induced by Chronic Fenofibrate Treatment

Deplanque, Dominique; Gelé, Patrick; Pétrault, Olivier; Six, Isabelle; Furman, Christophe; Bouly, Muriel; Nion, Stéphane; Dupuis, B; Leys, Didier; Fruchart, Jean‐Charles; Cecchelli, Roméo; Staels, Bart; Duriez, Patrick; Bordet, Régis

doi:10.1523/jneurosci.23-15-06264.2003

Cited by 220 publications

(209 citation statements)

References 45 publications

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“…The administration to aged mice of agents capable of activating the ␣ isoform of PPAR was found to restore the cellular redox balance (64). Additionally, a PPAR␣ activator, fenofibrate, protects against cerebral injury by antioxidant and anti-inflammatory mechanisms (65). This evidence suggests that PPAR␣ could be a new pharmacological target to control the neurodegenerative changes induced by oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Santos

Quintanilla²,

Toro

et al. 2005

Journal of Biological Chemistry

140

114

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Alzheimer disease is a neurodegenerative process that leads to severe cognitive impairment as a consequence of selective death of neuronal populations. The molecular pathogenesis of Alzheimer disease involves the participation of the ␤-amyloid peptide (A␤) and oxidative stress. We report here that peroxisomal proliferation attenuated A␤-dependent toxicity in hippocampal neurons. Pretreatment with Wy-14.463 (Wy), a peroxisome proliferator, prevent the neuronal cell death and neuritic network loss induced by the A␤ peptide. Moreover, the hippocampal neurons treated with this compound, showed an increase in the number of peroxisomes, with a concomitant increase in catalase activity. Additionally, we evaluate the Wy protective effect on ␤-catenin levels, production of intracellular reactive oxygen species, cytoplasmic calcium uptake, and mitochondrial potential in hippocampal neurons exposed to H 2 O 2 and A␤ peptide. Results show that the peroxisomal proliferation prevents ␤-catenin degradation, reactive oxygen species production, cytoplasmic calcium increase, and changes in mitochondrial viability. Our data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from A␤-induced degenerative changes.Peroxisomes are subcellular organelles found in most animal cells that perform diverse metabolic functions, including detoxification of reactive oxygen species (ROS) 2 through their matrix enzyme catalase (1-3) and regulation of the oxidative balance and fatty acid oxidation (4 -6). Peroxisomes are present in the cell bodies, dendrites, and presynaptic axon terminals of neuronal cells (7,8) as well as in growing neurites (9). Tau overexpression inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites (10), and it has been suggested that a loss of peroxisomes apparently makes neurons more vulnerable to oxidative stress (10). Peroxisome proliferators (PPs) are a class of structurally dissimilar industrial and pharmaceutical chemicals that were originally identified as inducers of peroxisome proliferation in rat and mouse hepatocytes (11,12). Several PPs have shown to bind to peroxisome proliferator-activated receptors (PPARs), these include Wy-14.643 (Wy), which binds with great affinity to PPAR␣ and induces a strong activation of this receptor (11). 4-Phenyl butyric (4-PB) is a PP that, in contrast to other PPs, is able to induce human peroxisome proliferation (13); however, the mechanism of peroxisome proliferation remains to be elucidated. According to Liu et al. (14), 4-PB activates PPARs in astrocytes; nevertheless, they suggested that peroxisome proliferation may be independent of PPAR␣ activation.Alzheimer disease (AD) is characterized by a progressive neurodegeneration associated with extracellular deposits of amyloid ␤-peptide (A␤) in the form of senile plaques (15,16). A␤ peptide acquires neurotoxic properties when it forms homo-oligomeric species (17) or heterooligomeric species with molecules associated with mature ...

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Section: Discussionmentioning

confidence: 99%

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Santos

Quintanilla²,

Toro

et al. 2005

Journal of Biological Chemistry

140

114

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“…In addition, Deplanque et al 43 have demonstrated that fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice and decreases infarct size volume in mice. This neuroprotective effect is partly associated with an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation, which is unrelated to an increase in eNOS expression.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Goya

Sumitani

et al. 2004

ATVB

162

111

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Objective-There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor ␣ (PPAR␣) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR␣ activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. Methods and Results-Bovine aortic endothelial cells were treated with the PPAR␣ activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR␣ action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. Conclusions-PPAR␣ activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR␣-mediated cardiovascular protection. Key Words: atherosclerosis Ⅲ endothelium Ⅲ nitric oxide Ⅲ vascular biology Ⅲ vasodilatation H ypolipidemic fibrates are pharmacological compounds that activate peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the nuclear hormone receptor superfamily. 1 These fibrates have been widely used as effective drugs lowering serum triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol. 2 There has been accumulating evidence showing that fibrates have favorable effects of slowing the progression of atherosclerosis and reducing the number of events of coronary heart diseases in high-risk patients. 3-5 PPAR␣ is known to be expressed in the liver, which is mainly involved in lipid and lipoprotein metabolism exerted by fibrates. 1 In addition, recent studies have shown that PPAR␣ is also expressed in the cardiovascular system, including heart and vascular wall component cells such as vascular endothelial, vascular smooth muscle, and monocyte cells, and performs a direct antiatherogenic and antiinflammatory action. 6 Staels et al have shown that PPAR␣ ligands inhibit interleukin (IL)-1-induced expression of IL-6, prostaglandin, and cyclooxygenase 2 in aortic smooth muscle cells. 7 These authors further showed that patients receiving fenofibrate, a potent fibrate, had lower plasma C-reactive protein, fibrinogen, and IL-6 concentrations. 7 Furthermore, it has been demonstrated that PPAR␣ activators inhibit cytokine-induced vascular cell adhesion molecule-1 (VCAM-1), 8,9 and thrombin-induced endothelin-1 expression 10 in vascular en...

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“…In the mouse stroke model, both fenofibrate (Deplanque et al, 2003) and OEA ( Figure 3) were found to have neuroprotective activities through PPARa, since they were unable to alter infarct volume in PPARa-deficient mice. Since the neuroprotective effects of PPARa were suggested to be independent of its well-known lipid-lowering effects (Deplanque et al, 2003), antioxidant and anti-inflammatory mechanisms might underlie PPARa-dependent neuroprotection.…”

Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidsmentioning

confidence: 99%

“…Since the neuroprotective effects of PPARa were suggested to be independent of its well-known lipid-lowering effects (Deplanque et al, 2003), antioxidant and anti-inflammatory mechanisms might underlie PPARa-dependent neuroprotection. A likely route for PPARa regulation of inflammatory responses is via repression of NFkB signalling (Staels et al, 1998).…”

Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidsmentioning

confidence: 99%

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Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

198

172

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Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

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Peroxisome Proliferator-Activated Receptor-α Activation as a Mechanism of Preventive Neuroprotection Induced by Chronic Fenofibrate Treatment

Cited by 220 publications

References 45 publications

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

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