Combination theraphy of betaine and fenofibrate against delayed neuronal

项目总结(见说明)： 迟发性神经恶化(DND)是动脉瘤性蛛网膜下腔出血(SAH)导致的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至10天。 尽管已经做出了很大的努力来预防这种神经疾病，但许多患者仍然对目前推荐的治疗没有反应。这个探索性项目将检验我们的假设，即甜菜碱(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药物。甜菜碱和非诺贝特分别用于治疗同型半胱氨酸尿症和血脂异常。在无脊椎动物中，甜菜碱促使生物体进入隐生状态，这是一种细胞的非代谢状态，以应对干燥、冻结和缺氧等不利环境。甜菜碱在哺乳动物细胞中也被证明对应激条件具有保护作用；然而，关于甜菜碱对应激神经系统的影响知之甚少。我们之前曾报道，调脂药物非诺贝特显著减少了缺血性中风小鼠的脑梗塞面积。这种神经保护伴随着脑微循环的改善、氧化应激的减轻和细胞黏附分子表达的抑制，这些都是SAH后DND的关键因素。我们最近的初步研究表明，甜菜碱和非诺贝特联合应用可减少脑梗塞体积，尽管单用该剂量的非诺贝特并不有效。这些发现表明至少有两种可能性：(1)甜菜碱单独可能具有保护作用；(2)甜菜碱可能抵消非诺贝特的不良影响。目的1将在小鼠SAH模型中测试甜菜碱单独治疗DND的SAH后治疗。目的2检测甜菜碱联合非诺贝特(SAH后)对SAH小鼠的影响。还将测量皮质血流灌注、行为结果、脑内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.