Mechanism for ischemic crosstoleance in central nervous system and its therapeutic application

我们先前已经证明，在缺血前重复高压氧(HBO)暴露(3.5绝对大气压(ATA))可显著减少短暂性前脑缺血后海马区CA1神经元的丢失。1)不同压力水平高压氧的作用；2)神经保护机制(用基因芯片技术)；3)生物学验证(用蛋白质合成抑制剂)。大鼠在100%氧气暴露(100%02组)和高压氧(分别为2ATA或3.5 MA，HBO-2ATA组，-3.5ATA组)或假手术组(Sham组)后12小时复制大鼠前脑缺血模型(8min)。3.5ATA-HBO对缺血损伤的海马神经元(存活神经元：68%)有最大的保护作用(假手术组：2.7%，100%02组：13.5%，2ATA-HBO组：44%)。基因芯片数据显示p75；lt；NTR&gt；，C/EBPδ，CD74的表达显著上调，其时程表达与高压氧诱导的神经保护相一致。蛋白质水平是…更多的LSO显著增加(分别为2.9、2.0和7.9)。此外，我们还观察了在高压氧暴露前给予蛋白质合成抑制剂山奈素(AM)或放线菌酮(CY)对神经保护的调节作用，这两种药物均可抑制高压氧诱导的神经保护作用，在给予AM和CY的大鼠中，神经元存活率分别为2.1%和8.9%。在每次AM-HBO治疗前给予p38 MAP激酶抑制剂SB203580(SB)，可恢复HBO诱导的神经保护作用。相比之下，在每次CY-HBO治疗前给予SB，HBO诱导的神经保护作用仅是边缘的。由于已知AM而不是CY具有p38丝裂原激活蛋白(P38MAP)激酶的激活特性，我们的结果提示高压氧诱导的神经保护机制参与了p38 MAP激酶的抑制。综上所述，高压氧诱导的神经保护作用是通过与神经营养素和炎症免疫系统相关的从头合成蛋白的合成以及对p38 MAP激酶的抑制来实现的。较少

We have previously demonstrated that repeated hyperbaric oxygen (HBO) exposure (3.5 absolute atmosphere (ATA)) prior to ischemia significantly reduced loss of hippocampal CAl neurons after transient forebrain ischemia. The present study examined 1) the effects of different pressure level of HBO, 2) neuroprotective mechanism (by using microarray technology), and 3) biological verification (by using protein synthesis inhibitor).Rats were subjected to forebrain ischemia (8 min)at 12 hours after five sessions of 100% oxygen exposure (100% 02 group) and HBO (at 2 ATA or 3.5 MA, (HBO-2ATA, -3.5ATA group, respectively)) or sham treatment (sham group). 3.5ATA-HBO maximally protected hippocampal CAl neurons (survived neurons : 68%) against ischemic damage(sham group : 2.7%, 100% 02 group : 13.5%, 2 ATA-HBO group : 44%).Microarray data showed significant up-regulation in p75^<NTR>, C/EBP δ, CD74, whose time-course expressions corresponded to HBO-induced neuroprotection. The protein levels were a … More lso significantly increased (2.9, 2.0, and 7.9, respectively). Further, we examined the modulation of neuroprotection by administering protein synthesis inhibitor, anisomycin (AM) or cycloheximide (CY) prior to HBO exposure, both of which inhibited HBO-induced neuroprotection, survived neuron being 2.1 and 8.9% in the rats treated with AM and CY, respectively. With administration of p38 MAP kinase inhibitor, SB203580 (SB), before each treatment with AM-HBO, HBO-induced neuroprotection was resumed. In contrast, with administration of SB before each treatment with CY-HBO, HBO-induced neuroprotection was only marginal. Because AM, but not CY, has been known to have activating property of p38 mitogen-activated protein (p38MAP) kinase, our results suggest that the mechanism of HBO-induced neuroprotection is involved in suppression of p38 MAP kinase.In conclusion, HBO induced neuroprotection against the neuronal damage in the hippocampal CAl following forebrain ischemia is mediated by de novo protein synthesis relevant to neurotrophin and inflammatory-immune system and to suppression of p38 MAP kinase. Less