Preconditioning paradigms and pathways in the brain

Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Cleveland Clinic Journal of Medicine (Impact Factor: 2.71). 04/2008; 75 Suppl 2(Suppl_2):S77-82. DOI: 10.3949/ccjm.75.Suppl_2.S77
Source: PubMed


Preconditioning is a phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. Preconditioning stimuli include ischemia, low doses of endotoxin, hypoxia, hypothermia and hyperthermia, cortical spreading depression, anesthetics, and 3-nitropropionic acid, among others. Understanding of the mechanisms underlying preconditioning has been elusive, but NMDA receptor activation, nitric oxide, inflammatory cytokines, and suppression of the innate immune system appear to have a role. Elucidation of the endogenous cell survival pathways involved in preconditioning has significant clinical implications for preventing neuronal damage in susceptible patients.

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Available from: Marc S Penn, Dec 23, 2013
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    • "Preconditioning of peripheral administration of 0.05–1.0 mg/kg LPS can cause transient neuroprotective responses against ischemia, stroke, and more destructive LPS treatments (Kitamura et al., 2004; Glezer et al., 2007; Shpargel et al., 2008; Imai et al., 2007). Treatment of 1 mg/kg LPS is shown to prime microglia toward differentiating into an M2 phenotype, which probably contribute to neuroprotection by establishing an anti-inflammatory, tissue-repairing microenvironment (Chen et al., 2012, 2014). "
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    ABSTRACT: Microglia are resident immunocompetent cells having important roles in innate immunity in the brains. In the present study, we found that a single lipopolysaccharide (LPS) administration significantly increased microglial proliferation in the fornix and dentate gyrus (DG) but not the cerebral cortex and corpus callosum of adult mice. LPS-induced microglial proliferation was especially robust at the white matter of the fornix. The density of microglia increased in the fornix and DG for roughly one week and returned to basal levels at least 20days after a single LPS administration. Consecutive LPS administration did not induce such dramatic increase of microglial proliferation in the fornix. The inhibition of vascular endothelial growth factor signaling by AZD2171 largely suppressed LPS-induced increase of microglial proliferation in the fornix. In conclusion, the present study indicates that the hippocampal neuronal system has a higher proliferative microglial capability against LPS-induced inflammatory administration compared with other brain regions. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Neuroimmunology 05/2015; 285:31-46. DOI:10.1016/j.jneuroim.2015.05.014 · 2.47 Impact Factor
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    • "Molecular mechanisms underlying preconditioning are not completely elucidated, but N-methyl-d-aspartate (NMDA) glutamate receptors, nitric oxide synthase, cytokines, oxidative stress and mitochondrial bioenergetics modulation and suppression of the innate immune system are some of the elements that have a pivotal role in such process [7] [8] [9] [10]. Particularly, NMDA and glutamate may act as chemical preconditioning agents in hippocampal slices [11], in cultured cells [12] and in vivo models of excitotoxicity [13]. "
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    ABSTRACT: N-methyl-D-aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A1 receptors (A1R), since blockade of A1R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A1R biology (i.e. expression, binding properties and functionality). Accordingly, we measured A1R expression in NMDA preconditioned mice (75mg/kg, i.p.; 24hours) and showed that neither the total amount of receptor, nor the A1R levels in the synaptic fraction was altered. In addition, the A1R binding affinity to the antagonist [(3)H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A1R functioning by measuring the A1R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT-1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A1R with the agonist CCPA (0.2mg/kg, i.p.). NMDA preconditioning or A1R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A1R modulates NMDA preconditioning-mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection. Copyright © 2014. Published by Elsevier B.V.
    Behavioural Brain Research 12/2014; 282. DOI:10.1016/j.bbr.2014.12.056 · 3.03 Impact Factor
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    • "Cerebral ischemic preconditioning (IPC) refers to a transient, sublethal ischemic event that results in tolerance to subsequent lethal cerebral ischemia. IPC is believed to trigger an intrinsic neuroprotective mechanism [1], [2]. Most studies of brain ischemic preconditioning in vivo and in vitro have been limited to neurons. "
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    ABSTRACT: Background Cerebral ischemic preconditioning (IPC) protects brain against ischemic injury. Activation of Toll-like receptor 3 (TLR3) signaling can induce neuroprotective mediators, but whether astrocytic TLR3 signaling is involved in IPC-induced ischemic tolerance is not known. Methods IPC was modeled in mice with three brief episodes of bilateral carotid occlusion. In vitro, IPC was modeled in astrocytes by 1-h oxygen-glucose deprivation (OGD). Injury and components of the TLR3 signaling pathway were measured after a subsequent protracted ischemic event. A neutralizing antibody against TLR3 was used to evaluate the role of TLR3 signaling in ischemic tolerance. Results IPC in vivo reduced brain damage from permanent middle cerebral artery occlusion in mice and increased expression of TLR3 in cortical astrocytes. IPC also reduced damage in isolated astrocytes after 12-h OGD. In astrocytes, IPC or 12-h OGD alone increased TLR3 expression, and 12-h OGD alone increased expression of phosphorylated NFκB (pNFκB). However, IPC or 12-h OGD alone did not alter the expression of Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) or phosphorylated interferon regulatory factor 3 (pIRF3). Exposure to IPC before OGD increased TRIF and pIRF3 expression but decreased pNFκB expression. Analysis of cytokines showed that 12-h OGD alone increased IFNβ and IL-6 secretion; 12-h OGD preceded by IPC further increased IFNβ secretion but decreased IL-6 secretion. Preconditioning with TLR3 ligand Poly I:C increased pIRF3 expression and protected astrocytes against ischemic injury; however, cells treated with a neutralizing antibody against TLR3 lacked the IPC- and Poly I:C-induced ischemic protection and augmentation of IFNβ. Conclusions The results suggest that IPC-induced ischemic tolerance is mediated by astrocytic TLR3 signaling. This reprogramming of TLR3 signaling by IPC in astrocytes may play an important role in suppression of the post-ischemic inflammatory response and thereby protect against ischemic damage. The mechanism may be via activation of the TLR3/TRIF/IRF3 signaling pathway.
    PLoS ONE 06/2014; 9(6):e99526. DOI:10.1371/journal.pone.0099526 · 3.23 Impact Factor
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