Effects of the PPAR-<i>α</i> Agonist Fenofibrate on Acute and Short-Term Consequences of Brain Ischemia

Ouk, Thavarak; Gautier, Sophie; Pétrault, Maud; Montaigne, David; Maréchal, Xavier; Masse, Ingrid; Devedjian, Jean-Christophe; Deplanque, Dominique; Bastide, Michèle; Nevière, Rémi; Duriez, Patrick; Staels, Bart; Pasquier, Florence; Leys, Didier; Bordet, Régis

doi:10.1038/jcbfm.2013.233

Cited by 61 publications

(42 citation statements)

References 33 publications

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“…Results are also consistent with reports showing that other PPARa agonists are protective against b-amyloid neurotoxicity (7,28). Finally, the importance of peroxisomes in stroke is highlighted by the fact that agents that increase peroxisomal proliferation (PPAR agonists) are clinically under evaluation for the treatment of stroke risk factors and experimentally as potential neuroprotective agents (8,23).…”

Section: Discussionsupporting

confidence: 78%

Peroxisomal Biogenesis in Ischemic Brain

Young

Nelson

Cheng

et al. 2015

Antioxidants & Redox Signaling

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Aims: Peroxisomes are highly adaptable and dynamic organelles, adjusting their size, number, and enzyme composition to changing environmental and metabolic demands. We determined whether peroxisomes respond to ischemia, and whether peroxisomal biogenesis is an adaptive response to cerebral ischemia. Results: Focal cerebral ischemia induced peroxisomal biogenesis in peri-infarct neurons, which was associated with a corresponding increase in peroxisomal antioxidant enzyme catalase. Peroxisomal biogenesis was also observed in primary cultured cortical neurons subjected to ischemic insult induced by oxygen-glucose deprivation (OGD). A catalase inhibitor increased OGD-induced neuronal death. Moreover, preventing peroxisomal proliferation by knocking down dynamin-related protein 1 (Drp1) exacerbated neuronal death induced by OGD, whereas enhancing peroxisomal biogenesis pharmacologically using a peroxisome proliferator-activated receptor-alpha agonist protected against neuronal death induced by OGD. Innovation: This is the first documentation of ischemia-induced peroxisomal biogenesis in mammalian brain using a combined in vivo and in vitro approach, electron microscopy, high-resolution laser-scanning confocal microscopy, and super-resolution structured illumination microscopy. Conclusion: Our findings suggest that neurons respond to ischemic injury by increasing peroxisome biogenesis, which serves a protective function, likely mediated by enhanced antioxidant capacity of neurons. Antioxid. Redox Signal. 22, 109-120.

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Section: Discussionsupporting

confidence: 78%

Peroxisomal Biogenesis in Ischemic Brain

Young

Nelson

Cheng

et al. 2015

Antioxidants & Redox Signaling

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“…In addition to PPAR ␥ , several fatty acids also bind to PPAR ␣ ( 72,73 ), and activation of this isoform of PPARs can afford neuroprotection from ischemic injury by antiinfl ammatory mechanism ( 74,75 ). In the present study, we cannot exclude the possibility that PPAR ␣ activation is involved in the actions of 12(S)-and 15(S)-HETE.…”

Section: Discussioncontrasting

confidence: 39%

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

Sun

Han

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org to form a series of biologically active lipid mediators ( 1, 2 ). In the CNS, 12/15-LOX expression has been described throughout the cerebrum, basal ganglia, and hippocampus ( 3, 4 ). Arachidonic acid (AA) is an important component of membrane lipids that can activate several signaling pathways directly by itself or by its metabolites ( 5 ). In nervous tissue, the major enzymatic route for AA metabolism is the 12/15-LOX pathway, and the principal metabolites are 12(S)-HETE and 15(S)-HETE ( 3, 4, 6, 7 ). The biological signifi cance of these metabolites of AA is that they have been proposed to play roles as second messengers in synaptic transmission and they are thought to be involved in learning and memory processes ( 8 ). In addition, 12(S)-HETE is known to act as an inhibitory neuromodulator by reducing voltage-sensitive calcium channel activity ( 9 ) and attenuating glutamate release and affi nity to its receptors ( 10-12 ).Brain ischemia triggers the massive release of free fatty acids from membrane stores, such as AA and DHA, and then the accumulation of lipid peroxides. 12/15-LOX is thought to be damaging because of its lipid-oxidizing properties, and the detrimental effects of 12/15-LOX have been documented by demonstrating the protection in the ischemic brain through 12/15-LOX inhibition or gene deletion ( 13-15 ). Several metabolites of 12/15-LOX, however, have neuroprotective and anti-infl ammatory qualities during brain ischemia. For example, 12/15-LOX metabolites derived from DHA and other -3 fatty acids inhibit cerebral ischemia-induced injury (16)(17)(18). This suggests 12/15-LOX and its metabolites may differ in their effects following cerebral ischemia.PPAR ␥ is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. This work was supported by grants from the National Natural Science Foundation of China (number 81070968 to L.S. and number 81401023 to Y-W.X.) and from the Tianjin Municipal Science and Technology Commission (number 13ZCZDSY01900 to Y.C.). The authors declare no confl icts of interest. Manuscript received 15 July 2014 and in revised form 12(S)-and 15(S)-HETE activate PPAR ␥ in ischemic brain 503animals survived the MCAO surgical procedure. Rats that did not demonstrate neurological defi cits during 90 min MCAO were excluded from further study. Animals dying prematurely during the reperfusion period or having subarachnoid hemorrhage at postmortem examination were also excluded. Measurements derived from these animals were not included in the present study. Drug treatmentEicosanoids, 12(S)-HETE and 15(S)-HETE, were products of Cayman Chemical (Ann Arbor, MI) and given 30 min before the onset of MCAO by icv injection. 12(S)-and 15(S)-HETE, supplied in ethanol at 1 mg/ml, were air-dried under a stream of nitrogen and dissolved in a 30% DMSO and 70% isotonic saline solution ( 35 ). Animals received either vehicle (30% DMSO-0.9% saline) or a single dose of 12(S)-or 15(S)-HETE at 10, 15, or 20 g ( ‫...

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“…In males, fenofibrate has been shown to improve initial stroke outcomes by reducing infarct volume and enhancing cerebral blood flow recovery after reperfusion (Guo et al 2010). Additionally, treatment with fenofibrate before stroke reduces the expression of ICAM-1 and VCAM-1, reduces adherent leukocytes, infiltrating neutrophils and regulates oxidative stress in the brain (Deplanque et al 2003; Ouk et al 2014a). Pre-treatment with fenofibrate also reduces neutrophils and gene expression of CXCL10, CXCL1 and SAA-1 in the liver after stroke (Losey et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Sex differences and the role of PPAR alpha in experimental stroke

et al. 2015

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Males and females respond differently to stroke. Moreover, females often experience worse long-term stroke outcomes. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist has been shown to improve stroke outcome and resolve neuroinflammation in male mice. The present study compares the effect of pretreatment with fenofibrate versus vehicle control in male and female mice during experimental stroke. Mice were treated with low-dose fenofibrate 30 minutes before and once a day for three additional days after stroke onset. We observed a reduction in infarct volume in male mice 96 hours post-stroke with low-dose fenofibrate pretreatment that was due to increase of an M2 macrophage phenotype in the brain and an increase in regulatory cells in the periphery. These outcomes were not replicated in females, likely due to the lower PPARα expression in cells and tissues in females vs males. We conclude that PPARα agonist treatment prior to stroke is neuroprotective in males but not females. These findings indicate PPARα as a probable mechanism of sex difference in stroke outcome and support the need for representation of females in stroke therapy research.

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Effects of the PPAR-α Agonist Fenofibrate on Acute and Short-Term Consequences of Brain Ischemia

Cited by 61 publications

References 33 publications

Peroxisomal Biogenesis in Ischemic Brain

Peroxisomal Biogenesis in Ischemic Brain

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

Sex differences and the role of PPAR alpha in experimental stroke

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