Anti-oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia

描述（由申请人提供）：细胞因子白血病抑制因子（LIF）已被证明是神经系统疾病（包括卒中）的潜在治疗分子。虽然LIF已被证明激活细胞存活途径，但确切的机制尚未阐明。我们的实验室已经表明，LIF保护培养的少突胶质细胞（OLs）从氧葡萄糖剥夺（OGD）。其机制之一是通过增加抗氧化酶金属硫蛋白-3（Mt3）和过氧化物氧还蛋白-4（Prdx 4）的表达来减少细胞外氧化应激。拟议的实验将阐明LIF信号传导机制，导致Mt3和Prdx 4的表达增加，以减少氧化应激。我们的假设是，LIF保护暴露于缺血条件下的少突胶质细胞通过抗氧化信号。该提案将利用缺血的体外模型来定义负责以下的信号通路： LIF的保护和抗氧化作用。此外，我们将扩大这些结果，以确定在体内是否延迟静脉注射LIF保护OL在大鼠脑局灶性脑缺血通过增加抗氧化活性。最后，我们将测试这种延迟给药对促进长期行为恢复的有效性。该提案将为其他动物研究提供数据，以检查LIF作为一种潜在的治疗方法，以扩大中风的治疗窗口。 公共卫生相关性：中风是美国的一个主要健康问题，只有一种FDA批准的治疗方法，治疗窗口有限。我们已经发现白血病抑制因子（LIF）通过增加抗氧化酶的表达从而减少氧化应激来保护神经细胞免受缺血。该提议中的实验将定义这种新的LIF诱导的信号通路，其在培养细胞和中风大鼠模型中均增强神经细胞存活。此外，将评估在临床相关时间点给予LIF增加中风后行为恢复的能力。因此，如果成功的话，这将是一种新的治疗方法，可以非侵入性地进行中风治疗。

DESCRIPTION (provided by applicant): The cytokine, leukemia inhibitory factor (LIF), has been shown to be a potential therapeutic molecule for neurological disorders, including stroke. While LIF has been shown to activate cellular survival pathways, exact mechanisms have yet to be elucidated. Our laboratory has shown that LIF protects cultured oligodendrocytes (OLs) from oxygen glucose deprivation (OGD). One of its mechanisms is by increasing the expression of antioxidant enzymes, metallothinein-3 (Mt3) and peroxiredoxin-4 (Prdx4), to reduce extracellular oxidative stress. The proposed experiments will elucidate the LIF signaling mechanisms leading to the increased expression of the Mt3 and Prdx4 to reduce oxidative stress. Our hypothesis is that LIF protects oligodendrocytes exposed to ischemic conditions via antioxidant signaling. This proposal will utilize an in vitro model of ischemia to define the signaling pathway responsible for the protective and antioxidant effects of LIF. Moreover, we will expand on these results to determine in vivo whether delayed i.v. administration of LIF protects OLs in the rat brain from focal cerebral ischemia through increased antioxidant activity. Lastly we will test this delayed administration for its efficacy to enhance long-term behavioral recovery. This proposal will provide the data for additional animal studies to examine LIF as a potential therapeutic to widen the treatment window for stroke. PUBLIC HEALTH RELEVANCE: Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. We have found that leukemia inhibitory factor (LIF) protects neural cells from ischemia through increasing the expression of anti-oxidant enzymes thus reducing oxidative stress. The experiments within this proposal will define this novel LIF-induced signal pathway that enhances neural cell survival both in cultured cells and in a rat model of stroke. Moreover, the administration of LIF at clinical relevant time points will be evaluated for its ability to increase behavioral recovery after stroke. Thus, if successful, this would be a novel therapeutic approach to stroke treatment that can be administered non-invasively.