Combination theraphy of betaine and fenofibrate against delayed neuronal

项目总结（见说明）： 迟发性神经功能恶化（DND）是蛛网膜下腔出血（SAH）导致死亡和残疾的主要原因。在人类中，这种并发症发生在破裂后7到10天。 尽管人们已经做出了很大的努力来预防这种神经系统疾病，但许多患者对目前推荐的治疗仍然没有反应。这个探索性项目将测试我们的假设，甜菜碱（三甲基甘氨酸）和非诺贝特的组合可能是这种神经系统疾病的潜在候选人。甜菜碱和非诺贝特已分别用于治疗同型胱氨酸尿症和血脂异常。在无脊椎动物中，甜菜碱驱使生物体进入隐生状态，这是细胞的一种无代谢状态，以应对不利的环境，如干燥，冷冻和缺氧。甜菜碱也被证明在哺乳动物细胞中对应激条件有保护作用;然而，关于甜菜碱对受到应激的神经系统的影响知之甚少。我们以前报道过，脂质正常化药物非诺贝特显著减少缺血性中风小鼠的梗死面积。这种神经保护作用伴随着脑微循环的改善、氧化应激的减轻和细胞粘附分子表达的抑制，所有这些都是SAH后DND的关键因素。我们最近的初步研究表明，甜菜碱和非诺贝特的组合减少梗死体积，虽然非诺贝特单独在该剂量是无效的。这些发现表明至少有两种可能性：（1）单独使用甜菜碱可能具有保护作用;（2）甜菜碱可能抵消非诺贝特的不良反应。目的1将在小鼠SAH模型中测试单独的甜菜碱对DND的SAH后治疗。目的2测定甜菜碱和非诺贝特联合应用对SAH后小鼠的作用。还将测量皮质灌注、行为结果、脑中微血栓形成和血浆同型半胱氨酸。

PROJECT SUMMARY (See instructions): Delayed neurological deterioration (DND) is a major cause of death and disability due to aneurismal subarachnoid hemorrhage (SAH). In humans, this complication occurs seven to ten days after the rupture. Although great efforts have been made for preventing this neurological condition, many patients remain unresponsive to the currently recommended treatments. This exploratory project will test our hypothesis that combination of betaine (trimethylglycine) and fenofibrate may be a potential candidate for this neurological disease. Betaine and fenofibrate have been prescribed for homocystinuria and dyslipidemia, respectively. In invertebrates, betaine drives organisms into cryptobiosis, an ametabolic state of cells, in response to adverse environment such as desiccation, freezing, and oxygen deficiency. Betaine has also been shown protective in mammalian cells against stressful conditions; however, little is known about the influence of betaine on the nervous system subjected to stress. We previously reported that the lipid normalizing drug fenofibrate significantly reduced infarct size in mice subjected to ischemic stroke. This neuroprotection was accompanied by improved cerebral microcirculation, attenuation of oxidative stress, and inhibition of cellular adhesion molecules expression, all of which are crucial factors to DND after SAH. Our recent preliminary studies showed that combination of betaine and fenofibrate reduced infarct volume although fenofibrate alone at that dose was not effective. These findings suggest at least two possibilities: (1) betaine alone might be protective; (2) betaine might counteract an adverse effect of fenofibrate. Aim 1 will test post-SAH treatment of betaine alone against DND in a mouse SAH model. Aim 2 will measure the effect of combination of betaine and fenofibrate (post-SAH) in mice after SAH. Cortical perfusion, behavioral outcome, microthrombosis formation in the brain, and plasma homocysteine will also be measured.