Neuronal PPARγ Deficiency Increases Susceptibility to Brain Damage after Cerebral Ischemia

Zhao, Xiurong; Strong, Roger; Zhang, Jie; Sun, Guanghua; Tsien, Joseph Zhuo; Cui, Zhenzhong; Grotta, James C.; Aronowski, Jaroslaw

doi:10.1523/jneurosci.5857-08.2009

Cited by 158 publications

(146 citation statements)

References 65 publications

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“…In accordance with this, HCA 2 activation has been shown to inhibit NF-kB activation in bone marrow-derived macrophages 46 . 15d-PGJ 2 is also an endogenous agonist of PPARg, a transcription factor with neuroprotective properties 47,48 . Via this mechanism, nicotinic acid is able to stimulate PPARg in human monocytes in vitro 24 .…”

Section: Discussionmentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

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Section: Discussionmentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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“…PPAR ␥ also plays a central role in dampening infl ammation via its inhibitory activity on expression of the proinfl ammatory mediators (19)(20)(21). Notably, treatment of rats with the ligands of PPAR ␥ can signifi cantly protect the brain from ischemic insult by acting against infl ammatory responses (22)(23)(24)(25)(26)(27). For example, in the transient middle cerebral artery occlusion (MCAO) model of the rat, administration of PPAR ␥ ligands troglitazone or pioglitazone dramatically decreased infarction volume, attenuated microglia activation, and reduced the expression of interleukin-1 ␤ (IL-1 ␤ ), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) ( 22 ).…”

Section: Western Blot Analysismentioning

confidence: 99%

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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“…These agents suppress the inflammatory response to cerebral ischemia, including reducing the expression of proinflammatory cytokines and influx of systemic inflammatory cells and increasing the expression of free radical scavengers. 59,60 Agents that act on multiple sites on the mitochondria to reduce organelle dysfunction are more likely to be effective, since if only one pathway of mitochondrial injury is targeted, other avenues of injury will remain susceptible. Combination therapy may prolong the temporal therapeutic window.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Reperfusion brain injury

Pundik

Sundararajan

2012

Neurology

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Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis.The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellular milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other supporting cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia.In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a

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Neuronal PPARγ Deficiency Increases Susceptibility to Brain Damage after Cerebral Ischemia

Cited by 158 publications

References 65 publications

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

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

Reperfusion brain injury

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