The role of PPAR activation during the systemic response to brain injury

Losey, Patrick; Ladds, Emma; Laprais, Maud; Geuvel, Borna; Burns, Lindsay H.; Bordet, Régis; Anthony, Daniel C.

doi:10.1186/s12974-015-0295-7

Cited by 24 publications

(22 citation statements)

References 56 publications

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“…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). PPARα agonist, WY14643, exhibits a similar reduction of adhesion molecule expression, oxidative stress and iNOS expression when used as a pretreatment to stroke (Collino et al 2006).…”

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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Section: Discussionmentioning

confidence: 99%

Sex differences and the role of PPAR alpha in experimental stroke

et al. 2015

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“…PPARα agonist improves stroke outcome by reducing adhesion molecule expression in the brain and, thereby, limiting early neutrophil infiltration, reducing inflammatory factors, regulating oxidative stress, and increasing cerebral blood flow (Deplanque et al, 2003; Collino et al, 2006; Guo et al, 2010; Ouk et al, 2013, 2014; Losey et al, 2015). However, PPARα agonists did not have the same protective effect in female mice subjected to MCAO (Dotson et al, 2016b).…”

Section: Translation Of Therapies To Both Sexesmentioning

confidence: 99%

Sex differences in the immune response to experimental stroke: Implications for translational research

Dotson

Offner

2016

J of Neuroscience Research

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Ischemic stroke is a leading cause of death and disability in the United States. It is known that males and females respond differently to stroke. Depending on age, the incidence, prevalence, mortality rate, and disability outcome of stroke differ between the sexes. Females generally have strokes at older ages than males and, therefore, have a worse stroke outcome. There are also major differences in how the sexes respond to stroke at the cellular level. Immune response is a critical factor in determining the progress of neurodegeneration after stroke and is fundamentally different for males and females. Additionally, females respond to stroke therapies differently from males, yet they are often left out of the basic research that is focused on developing those therapies. With a resounding failure to translate stroke therapies from the bench to the bedside, it is clearer than ever that inclusion of both sexes in stroke studies is essential for future clinical success. This Mini-Review examines sex differences in the immune response to experimental stroke and its implications for therapy development.

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“…Moreover, studies have found that cleaved caspase-3 activity increased gradually within 24 hours in the infarct core after transient MCAo; but the activity was overall lower in the nonperfused core after permanent occlusion, suggesting that caspase-3 activity depends on reperfusion by the fact that free radicals generated during reperfusion (6,14,18). So at our study, we demonstrated the ischemia-reperfusion MCAo rat model to observe the cleaved caspase-3 association with ischemic infarct volume.…”

Section: Middle Cerebral Artery Occlusion (Mcao)mentioning

confidence: 48%

“…Previous data showed that the post-ischemic activation of NF-κβ dependent genes has a key modulation on proinflammatory and proapoptotic study showed that pretreatment with fenofibrate improved the penumbral cerebral blood flow during MCAo (17). Recently, Losey et al observed that a 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the acute phase response (14).…”

Section: Effect Of Fenofibrate On Body Weightmentioning

confidence: 99%

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Neuroprotective effects of chronic fenofibrate treatment via modulating the immunoreactivity of cleaved caspase-3 in stroke induced by transient middle cerebral occlusion rat model

Altıntaş¹,

Altintas²,

Aydın³

et al. 2016

Turkish Neurosurgery

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AIm: Current stroke therapies include lipid-lowering drugs, which reduce inflammation and serve to stabilize the atherosclerotic plaque to demonstrate better outcome and neuroprotection. Peroxisome proliferator activated receptors (PPAR) α regulates lipid homeostasis and is a target of fibrates, which have a neuroprotective function by various mechanisms. In this study, we aimed to evaluate the role of the PPARα agonist, fenofibrate, in the modulation of cleaved caspase-3 immunoreactivity and at the final infarct volume in an experimental ischemia/reperfusion rat model by induced transient proximal middle cerebral artery occlusion. mATERIAl and mEThODS: A total of 65 male Sprague Dawley rats were allocated into 4 groups; sham (n =5), experiment 1 (n=20), experiment 2 (n=20), experiment 3 (n=20). All experiment groups were divided to 3 subgroups in order to evaluate the final infarct volume at 24 th hour (n=5) and the immunoreactivity of cleaved caspase -3 at different time periods [at first hour (n=5), at 6 th hour (n=5), at 24 th hour (n=5)] after transient middle cerebral artery occlusion (MCAo). At the study, the experiment groups (Experiment 1 and Experiment 2) were received the fenofibrate-diet during 14 days before ischemia procedure. All animals were sacrificed at 24 th hours after MCAo. Infarction volumes were calculated from 2,3,5,triphenyltetrozolium chloride (TTC)-stained brain sections. RESUlTS:We found that fenofibrate-therapy reduced significantly more body weight than the other experiment groups (p<0.05). At the time intervals, a decrease of immunoreactivity of cleaved caspase-3 was significantly observed with fenofibrate therapy after MCAo (p<0.05). Chronic fenofibrate treatment before cerebral ischemia significantly reduced the infarction size after MCAo compared with the other groups (respectively; p = 0.011 and p< 0.000). CONClUSION:Fenofibrate treatment has neuroprotective effects on middle cerebral artery infarcts.

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The role of PPAR activation during the systemic response to brain injury

Cited by 24 publications

References 56 publications

Sex differences and the role of PPAR alpha in experimental stroke

Sex differences and the role of PPAR alpha in experimental stroke

Sex differences in the immune response to experimental stroke: Implications for translational research

Neuroprotective effects of chronic fenofibrate treatment via modulating the immunoreactivity of cleaved caspase-3 in stroke induced by transient middle cerebral occlusion rat model

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