The Akt-Endothelial Nitric Oxide Synthase Pathway in Lipopolysaccharide Preconditioning-Induced Hypoxic-Ischemic Tolerance in the Neonatal Rat Brain

Lin, Hsiang Yin; Wu, Chao‐Liang; Huang, Chao

doi:10.1161/strokeaha.109.574004

Cited by 40 publications

(31 citation statements)

References 24 publications

(42 reference statements)

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“…In future studies, it will be important to investigate whether continued or sustained exposure to low-dose LPS during induction of HI has any further effect on the evolution of injury. The present findings of delayed protection support the view that preconditioning or cross-tolerance induces a transient window of protection which is dependent on gene induction and de novo protein synthesis, consistent with in vitro [69,70] and in vivo [71,72,73,74,75] neonatal and adult rat models of ischemia.…”

Section: Discussionsupporting

confidence: 88%

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Dhillon

Gunn

Jung³

et al. 2015

Dev Neurosci

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Acute exposure to subclinical infection modulates subsequent hypoxia-ischemia (HI) injury in a time-dependent manner, likely by cross-talk through Toll-like receptors (TLRs), but the specific pathways are unclear in the preterm-equivalent brain. In the present study, we tested the hypothesis that repeated low-dose exposure to lipopolysaccharide (LPS) before acute ischemia would be associated with induction of specific TLRs that are potentially neuroprotective. Fetal sheep at 0.65 gestation (term is ∼145 days) received intravenous boluses of low-dose LPS for 5 days (day 1, 50 ng/kg; days 2-5, 100 ng/kg) or the same volume of saline. Either 4 or 24 h after the last bolus of LPS, complete carotid occlusion was induced for 22 min. Five days after LPS, brains were collected. Pretreatment with LPS for 5 days decreased cellular apoptosis, microglial activation and reactive astrogliosis in response to HI injury induced 24 but not 4 h after the last dose of LPS. This was associated with upregulation of TLR4, TLR7 and IFN-β mRNA, and increased fetal plasma IFN-β concentrations. The association of reduced white matter apoptosis and astrogliosis after repeated low-dose LPS finishing 24 h but not 4 h before cerebral ischemia, with central and peripheral induction of IFN-β, suggests the possibility that IFN-β may be an important mediator of endogenous neuroprotection in the developing brain.

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Section: Discussionsupporting

confidence: 88%

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Dhillon

Gunn

Jung³

et al. 2015

Dev Neurosci

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“…It was shown that systemic LPS-or ischemiainduced preconditioning causes neuroprotection as a long term outcome through mechanisms involving several different pathways including COX-2, nitric-oxide synthase, and reactive oxygen species (47)(48)(49). Interestingly, also in the hypoxic slice culture model by Kim et al (47) COX-2 activity was crucial for preconditioning-induced neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory Role of Microsomal Prostaglandin E Synthase-1 in a Model of Neuroinflammation

Brenneis

Coste

Altenrath

et al. 2011

Journal of Biological Chemistry

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A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E 2 (PGE 2 ). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE 2 has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE 2 synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of Eprostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI 2 receptor (IP), thromboxane A 2 receptor (TP), PGD 2 receptor (DP), and PGF 2 receptor (FP), efficiently blocked LPS-induced tumor necrosis factor ␣ (TNF␣) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNF␣, interleukin 1␤ (IL-1␤), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNF␣ and IL-1␤ synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE 2 followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE 2 in resolution of neuroinflammation.Neurodegenerative disorders, including Alzheimer and Parkinson disease, multiple sclerosis, and spinal cord or peripheral nerve injury, are associated with neuroinflammation (1, 2). Its initiation, maintenance and resolution are regulated by various cell types, including resident microglia, astroglia, and oligodendrocytes as well as invading blood leukocytes. Lipopolysaccharide (LPS) has traditionally been used to simulate innate immune responses in the central nervous system (CNS) by activating toll-like receptor-4 of microglia (3). Upon activation, microglia release inflammatory mediators such as cytokines, chemokines, free radicals, nitric oxide, or prostaglandins (4). One of the earliest events during LPS-induced neuroinflammation is the synthesis and release of the proinflammatory cytokine TNF␣ by microglia, which reaches maximum concentrations 2-8 h after the initial inflammatory stimulus (5). In effector cells, TNF␣ induces the expression of multiple proteins that further enhance the inflammatory response, including cyclooxygenase-2 (COX-2) and the functionally coupled microsomal PGE 2 synthase-1 (mPGES-1) 2 (6, 7). After 24 h, TNF␣ levels decrease to base-line levels whereas the activation of glia persists for several days (8). The mechanisms controlling the precise...

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“…LPS preconditioning involves injecting low doses of this potent bacterial endotoxin in rodents before the final insult (hypoxia ischemia, MCAO), which later imparts IT in the brain [75,132]. Yet, another mode of CPC involves estrogen preconditioning [36].…”

Section: Preconditioning Agentsmentioning

confidence: 99%

Cerebral Ischemic Preconditioning: the Road So Far…

Sangwan

Sharma

et al. 2015

Mol Neurobiol

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Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain.

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The Akt-Endothelial Nitric Oxide Synthase Pathway in Lipopolysaccharide Preconditioning-Induced Hypoxic-Ischemic Tolerance in the Neonatal Rat Brain

Cited by 40 publications

References 24 publications

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Anti-inflammatory Role of Microsomal Prostaglandin E Synthase-1 in a Model of Neuroinflammation

Cerebral Ischemic Preconditioning: the Road So Far…

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