Endogenous brain protection-models, gene expression, and mechanisms

High-Throughput Biology, Discovery Research, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA.
Methods in molecular medicine 02/2005; 104:105-84. DOI: 10.1385/1-59259-836-6:105
Source: PubMed


Almost all injurious stimuli, when applied below the threshold of producing injury, activate endogenous protective mechanisms that significantly decrease the degree of injury after subsequent injurious stimuli. For example, a short duration of ischemia (i.e., ischemic preconditioning [PC]) can provide significant brain protection to subsequent long-duration ischemia (i.e., ischemic tolerance [IT]). PC/IT has recently been shown in human brain, suggesting that learning more about these endogenous neuroprotective mechanisms could help identify new approaches to treat patients with stroke and other central nervous system disorders/injury. This chapter provides a brief overview of PC/IT research, illustrates the types of data that can be generated from in vivo and in vitro models to help us understand gene and protein expression related to induced neuroprotective mechanisms, and emphasizes the importance of future research on this phenomenon to help discover new mechanisms and targets for the medical treatment of brain and other end-organ injuries.

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    ABSTRACT: Transient cerebral ischemia leads to protein aggregation mainly in neurons destined to undergo delayed neuronal death after ischemia. This study utilized a rat transient cerebral ischemia model to investigate whether ischemic preconditioning is able to alleviate neuronal protein aggregation, thereby protecting neurons from ischemic neuronal damage. Ischemic preconditioning was introduced by a sublethal 3 min period of ischemia followed by 48 h of recovery. Brains from rats with either ischemic preconditioning or sham-surgery were then subjected to a subsequent 7 min period of ischemia followed by 30 min, 4, 24, 48 and 72 h of reperfusion. Protein aggregation and neuronal death were studied by electron and confocal microscopy, as well as by biochemical analyses. Seven minutes of cerebral ischemia alone induced severe protein aggregation after 4 h of reperfusion mainly in CA1 neurons destined to undergo delayed neuronal death (which took place after 72 h of reperfusion). Ischemic preconditioning reduced significantly protein aggregation and virtually eliminated neuronal death in CA1 neurons. Biochemical analyses revealed that ischemic preconditioning decreased accumulation of ubiquitin-conjugated proteins (ubi-proteins) and reduced free ubiquitin depletion after brain ischemia. Furthermore, ischemic preconditioning also reduced redistribution of heat shock cognate protein 70 and Hdj1 from cytosolic fraction to protein aggregate-containing fraction after brain ischemia. These results suggest that ischemic preconditioning decreases protein aggregation after brain ischemia.
    Preview · Article · Feb 2005 · Neuroscience
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