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• W2023756758 abstract "Endogenous mechanisms of neuroprotection are those that have been evolutionarily conserved and may therefore be strong candidates to mimic as therapeutics. We have pursued this approach to neuroprotection in both brain ischemia and in epileptic brain injury. Patterns are emerging that lead to a new understanding of adaptive mechanisms in brain. Brief periods of ischemia (TIAs) in a given arterial distribution attenuate stroke injury in that region in both rodents and humans (Chen et al., 1996; Weih et al., 1999). This endogenous neuroprotective mechanism is that of ischemic tolerance or preconditioning. This “classic” tolerance is protein synthesis dependent, requires 24 h to develop, is maximal at three days, and lasts about one week. As tolerance is protein synthesis dependent, we used microarray techniques to investigate tolerance at the transcriptional level. We looked at gene regulation in mice subjected to either preconditioning ischemia alone (TIA), prolonged ischemia alone (stroke), or preconditioning ischemia followed by prolonged ischemia (ischemic tolerance). We discovered that the genes induced by the preconditioning stimulus had minimal overlap with the genes induced by prolonged ischemia. Further, the brains subjected to preconditioning ischemia followed by prolonged ischemia, that is, the brains demonstrating neuroprotection of tolerance, had regulated genes distinct from the other two groups. In other words, when the preconditioned brain was subjected to severe ischemia, it responded to ischemia with a unique group of regulated genes that produced the neuroprotected phenotype. This gene group was unique from that occurring in brain by either preconditioning or severe ischemia alone. We called this phenomenon reprogramming (Stenzel-Poore et al., 2003). Thus, brief ischemia, reprogrammed the brain to respond differently to a subsequent episode of severe ischemia, and that different response changed the outcome from cell death to cell survival. Gene regulation can be either that of induction or suppression. One would assume that protection would be associated with induction of protective genes. Interestingly gene suppression predominated in the protected phenotype. The gene down-regulation targeted high-energy utilizers such as channel proteins, metabolic pathways and transporters. We likened this profile to that of hibernation. Prior seizures can attenuate neuronal brain injury resulting from subsequent seizures. Such epileptic tolerance has features in common with ischemic tolerance. Epileptic tolerance is observed in a delayed manner following preconditioning seizures and tolerance attenuates both cell death and nonlethal cell injury (Sasahira et al., 1995; Plamondon et al., 1999). To further study mechanisms of epileptic tolerance, we utilized an in vitro model of seizures that we have developed, based on the kynurenic acid withdrawal model of Furshpan and Potter (1989). Seizures are induced by the withdrawal of kynurenic acid and MgCl2 from chronically treated hippocampal neuronal cultures. Addition of MK801 blocks cell death during seizures but does not block seizure-like activity (Meller et al., 2003). Therefore, we used a seizure in the presence of MK801 to precondition hippocampal cells. Such preconditioned hippocampal neurons reduced cell death following a seizure that would normally be harmful (Fig. 1). Using this model, we investigated the genomic signature of epileptic tolerance. Regulation of gene expression in epileptic tolerance. Top: Venn diagram of genes regulated, 24 h following seizure. Note minimal overlap of genes in each treatment group. Bottom: Regulation of genes by ontology and induction or suppression of transcription, 24 h following seizure. RNA samples were isolated at 4 and 24 h after seizure, preconditioning seizure, preconditioning seizure followed by injurious seizure, or from control treated cultures. Gene expression was determined by genechip analysis using Affymetrix 230 v2.0 murine chips (Affymetrix, Santa Clara, CA, U.S.A.) and data analyzed using GeneSifter Microarray data analysis software (vizXlabs, Seattle, WA, U.S.A.). Similar to our ischemic tolerance model, we discovered that genes induced by the preconditioning stimuli had minimal overlap with genes induced by injurious seizures. Interestingly, we also observed minimal overlap of these two groups of genes with those regulated in cells subject to preconditioning seizures, followed by an injurious seizure. Therefore, as in ischemic tolerance, epileptic preconditioning also results in a reprogramming of the neuronal response to normally injurious stimuli. Further ontological analysis of the 24-h subset of regulated genes suggests that the processes regulated by preconditioning seizures vary from those regulated by preconditioning ischemia. Unlike preconditioning ischemia, there are a similar number of genes showing increased expression, compared to decreased expression. While ischemic tolerance resulted in the regulation of genes associated with hibernation like phenotype of the downregulation of energy dependent processes, epileptic preconditioning appears to regulate processes involved with metabolism, cell cycle, and signal transduction. These data, and other data from lipopolysaccharide (LPS) induced ischemic tolerance in brain (Stenzel-Poore et al., 2007), and distinct genetic programs induced by anesthetic and ischemic preconditioning of the heart (da Silva et al., 2004; Sergeev et al., 2004) suggest that the nature of the preconditioning stimulus determines the neuroprotective phenotype. However, the induced-neuroprotection is broadly applicable to injury. Epileptic seizures and ischemia can precondition the brain against either injury. For example, brief kainic acid seizures can protect against brain injury from global ischemia and brief periods of global ischemia can protect against seizure-induced brain injury (Plamondon et al., 1999). Many examples of such cross-tolerance have now been recognized (Dirnagl et al., 2003; Gidday, 2006). While the specific genes involved in these processes may differ, the resultant effect appears to be the same, reduction in cell death resulting from the exposure to a normally harmful stimulus. Translation to patients is now the challenge." @default.
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• W2023756758 date "2007-10-30" @default.
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• W2023756758 title "Endogenous mechanisms of neuroprotection" @default.
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• W2023756758 doi "https://doi.org/10.1111/j.1528-1167.2007.01356.x" @default.
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