Neuronal expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and 15d-prostaglandin J2—Mediated protection of brain after experimental cerebral ischemia in rat

Ou, Zhishuo; Zhao, Xiurong; Labiche, Lise A.; Strong, Roger; Grotta, James C.; Herrmann, Oliver; Aronowski, Jaroslaw

doi:10.1016/j.brainres.2006.04.062

Cited by 76 publications

(70 citation statements)

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“…In the ischemic brain, PPAR ␥ immunoreactivity has been evidenced mainly in neurons ( 36,40 ) and also in astrocytes, microglia ( 57 ), and other cells ( 58 ). In our data, most of the cells with 12/15-LOX staining also demonstrated positive immunoreactivity for the neuronal marker, which is consistent with the previous reports ( 14,15,59 ).…”

Section: Discussionsupporting

confidence: 92%

“…For this purpose, the nuclear extract proteins from the rats treated with 12(S)-HETE, 15(S)-HETE, or vehicle were incubated in a 96-well plate immobilized with an oligonucleotide containing the PPRE . As demonstrated in Finally, we assessed PPAR ␥ transcriptional activity in neuronal cells, the cell type in which both 12/15-LOX and PPAR ␥ are predominantly expressed ( 14,15,36,40 ) and PPAR ␥ defi ciency increases susceptibility to brain ischemic damage ( 26 ). Primary cultured cortical neurons were transiently transfected with a luciferase reporter construct containing three copies of a consensus PPRE and treated with increasing concentrations of 12(S)-or 15(S)-HETE.…”

Section: Ppar ␥ Antagonist Gw9662 Dose-dependently Reverses the Supmentioning

confidence: 99%

“…For example, lipoxin A4, one of the AA products formed via 5-LOX, has been shown to have PPAR ␥ agonistic actions and neuroprotection following experimental stroke, and to increase PPAR ␥ transcriptional activity in isolated nuclei from rat brain cortex ( 46 ). The similar protective effects and PPAR ␥ activation can be produced by 15d-PGJ2, one of the AA-derived products via the cyclooxygenase pathway, treated during brain ischemia in vivo and in vitro ( 36,47,48 ). Even AA, from which 12(S)-and 15(S)-HETE are derived, has been shown to be neuroprotective against oxidative stress on hippocampal slices through a process involving PPAR ␥ signaling ( 33 ).…”

Section: /15-lox-derived Metabolites 12(s)-and 15(s)-hetementioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Ppar ␥ Antagonist Gw9662 Dose-dependently Reverses the Supmentioning

confidence: 99%

Section: /15-lox-derived Metabolites 12(s)-and 15(s)-hetementioning

confidence: 99%

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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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“…172 Cerebral ischemia increases PPAR␥ expression in neurons and microglia, but at the same time DNA binding of PPAR␥ is reduced. 174 DNA binding is restored by PPAR␥ ligands, 170,174,175 and these agents have been shown to reduce ischemic injury in rodent stroke models. 176 Treatment with PPAR␥ ligands reduces microglia and macrophage activation and migration to the periinfarct regions, 177,178 attenuates the expression of ICAM-1, MMP-9, IL-1␤, COX-2, TNF␣, and iNOS, and suppresses production of reactive oxygen species.…”

Section: Ppar␥mentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…PPAR mRNA is up-regulated in ischemic brain, especially in the peri-infarct area. Increased PPAR mRNA was detected in the infarcted brain as early as 6 h following focal ischemia (Ou, Zhao et al 2006), and PPAR immunopositive neurons were detected between 4 h and 14 days, whereas in neurons and microglia only transiently at 12 h in the post-ischemic brain (Zhao, Patzer et al 2005;Victor, Wanderi et al 2006). The beneficial role of PPAR / in stroke has been demonstrated by two different studies in which PPAR / knockout mice subjected to cerebral IRI showed significantly larger infarct size than wild-type littermates (Pialat, Cho et al 2007).…”

Section: Ppars and Cerebral Ischemia 41 Experimental Data On The Effmentioning

confidence: 93%

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

Benetti¹,

Patel²,

Collino³

2012

Advances in the Preclinical Study of Ischemic Stroke

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Neuronal expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and 15d-prostaglandin J2—Mediated protection of brain after experimental cerebral ischemia in rat

Cited by 76 publications

References 50 publications

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

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

Microglial Activation in Stroke: Therapeutic Targets

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

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