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• W2085203835 abstract "Using a mild insult to induce endogenous neuroprotective mechanisms is known as preconditioning. When followed by a severe insult, or challenge, preconditioning results in a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance is observed in ischemia, seizure, and infection and can be induced when the severe insult is preceded by a mild insult of the same or different type. Classical tolerance requires new protein synthesis and confers delayed and temporary neuroprotection, taking hours to develop, peaking over the course of 1–3 days, and then abating (Barone et al., 1998). In rodents and humans, transient ischemic attacks (TIAs) attenuate the injury sustained from an ensuing stroke (Chen et al., 1996; Weih et al., 1999). We used microarray analysis to profile the transcriptional changes that occur in the mouse cortex after ischemic preconditioning [15-min middle cerebral artery occlusion (MCAO)], ischemic challenge (60-min MCAO), and ischemic tolerance (15-min MCAO followed 72 h later by 60-min MCAO). The analysis showed that the genes regulated by preconditioning and the genes regulated by challenge were different. Moreover, genes regulated in tolerance were distinct from those regulated by either preconditioning or challenge. Accordingly, we propose that preconditioning reprograms the brain’s response to challenge, altering the transcriptional response, and thereby producing a neuroprotected phenotype (Stenzel-Poore et al., 2003). The reprogrammed response to ischemic challenge induced by ischemic preconditioning begins to elucidate putative mechanisms of endogenous neuroprotection. In ischemic tolerance, gene expression is predominantly suppressed. Ion channels, transporters, and metabolic pathways are particularly influenced. This is reminiscent of the endogenous neuroprotective mechanisms that allow hibernating animals to survive periods of prolonged oxygen and glucose deprivation (Storey & Storey, 1990; Hochachka et al., 1996). The endotoxin lipopolysaccharide (LPS) is a surface component of bacteria that triggers an inflammatory response through its interaction with toll-like receptor 4 (TLR4). Exposure to a low dose of LPS preconditions the brain and can produce ischemic tolerance (Tasaki et al., 1997). We used microarray analysis to profile the mouse cortex after endotoxin preconditioning (5-μg LPS), ischemic challenge (60-min MCAO), and LPS–ischemic cross-tolerance (5-μg LPS followed 72 h later by 60-min MCAO). The results support our conclusion that preconditioning achieves neuroprotection by reprogramming the transcriptional response to a severe insult. A majority of genes regulated in LPS-induced ischemic tolerance were not regulated in ischemic challenge (Stenzel-Poore et al., 2007). The nature of the reprogrammed response to ischemic challenge induced by LPS preconditioning offers further insight into endogenous neuroprotection. Whereas ischemic preconditioning suppresses expression of genes influencing metabolism and transport, LPS preconditioning modulates inflammatory mediators, inducing neuroprotective cytokines and repressing proinflammatory molecules. This suggests that the preconditioning stimulus provides neuroprotection by reprogramming particular aspects of the response to challenge, specifically those intrinsic to the preconditioning stimulus (Davis & Patel, 2003; Stenzel-Poore et al., 2007). Cell damage and death caused by a prolonged seizure diminishes when preceded by a brief, mild seizure. Various stimuli, including kindling, bicuculline, kainic acid, and electroshock effectively precondition the brain against status epilepticus (Kelly & McIntyre, 1994; Sasahira et al., 1995; Najm et al., 1998; Plamondon et al., 1999; Andre et al., 2000; Kondratyev et al., 2001; Borges et al., 2007; Hatazaki et al., 2007). We have used microarray analysis to profile the transcriptional changes that occur in the CA3 subfield of the mouse hippocampus after epileptic challenge (intraamygdala administration of kainic acid) and after epileptic tolerance (systemic administration of kainic acid followed 24 h later by intraamygdala administration of kainic acid). In contrast to ischemia, many of the same genes were regulated by both epileptic challenge and epileptic tolerance. However, a substantial subset of genes was regulated only by epileptic tolerance, and, notably, these differentially regulated genes were predominantly suppressed (Jimenez-Mateos et al., 2008). Prominent among the suppressed genes were those whose products participate in calcium signaling, synaptic function, long-term potentiation, and excitatory neurotransmission. We conclude that reprogramming, albeit to a less-pronounced degree, underlies the neuroprotection provided by seizure preconditioning. Moreover, seizure preconditioning specifically promotes an anti-excitotoxic phenotype, particularly apposite to the inducing stimulus, as an antiinflammatory phenotype is to LPS and a hypometabolic phenotype is to ischemia. We note that these phenotypes are appropriate to the nature of the preconditioning stimulus and not to the nature of the challenging stimulus. As an endogenous neuroprotective mechanism this can be understood as a first insult priming the brain to respond advantageously in the likelihood of a second insult of the same kind. Yet the brain appears also to respond advantageously to a second insult of a different kind. The basis for this is not yet clear. Our microarray studies make apparent that the response to any brain challenge is complex, engaging numerous and diverse pathways. Therefore, modulating metabolism, inflammation, or excitoxicity could provide a measure of protection against diverse insults that disrupt these functions to greater and lesser degrees. Our studies show that seizure preconditioning alters the expression of inflammatory mediators after epileptic challenge in a manner similar to LPS preconditioning (M.B. Johnson and R.P. Simon, unpublished results). Consequently, different preconditioning stimuli may activate common neuroprotective pathways. There may also be shared neuroprotective mechanisms not detectable at the transcriptional level. The ongoing task is to apply our understanding of endogenous neuroprotection to therapy while continuing to elucidate mechanisms. The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this paper is consistent with those guidelines. Disclosure: The authors have no conflicts of interest to disclose." @default.
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• W2085203835 date "2009-11-18" @default.
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• W2085203835 title "Endogenous neuroprotective mechanisms in the brain" @default.
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• W2085203835 doi "https://doi.org/10.1111/j.1528-1167.2009.02359.x" @default.
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