PATHOGENESIS OF OSMOTIC INDUCED DEMYELINATION

渗透性脱髓鞘的发病机制

• 批准号: 2714471
• 负责人: SHELDON ADLER
• 金额: $ 28.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-30 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2714471
• 关键词: albumins; bioenergetics; blood brain barrier; brain metabolism; chronic disease /disorder; complement; disease /disorder model; hyponatremia; immunocytochemistry; immunoglobulin G; laboratory rat; leukocytes; membrane permeability; myelinopathy; nuclear magnetic resonance spectroscopy; osmotic pressure

DESCRIPTION: (Adapted from Applicant's Abstract) Rapid correction of hyponatremia, a common medical condition, may cause pontine and extrapontine demyelination in both animals and humans. Recent reports reveal that rapid increases in plasma sodium and osmolality disrupt the blood-brain barrier (BBB) of chronic hyponatriemic rats at a lower plasma osmolality values than in either acute hyponatriemic or normonatriemic control rats; that rapid increases in plasma sodium markedly increased cerebral perfusion; and that disruption of the BBB occurring after rapid correction of chronic hyponatremia preceded and appeared to be related to the development of demyelination. The overall study objective, therefore, is to determine how these alterations in BBB permeability and cerebral perfusion relate to the subsequent development of neurologic symptoms and demyelination which follows rapid correction of chronic hyponatremia. Experiments will use a stable CHN rat model which on rapid correction of hyponatremia produces demyelination in 50-60 percent of rats. Uncorrected CHN rats will serve as controls. Studies will include: 1) immunocytochemical analyses of brains for IgG and albumin to determine when and where BBB permeability increases during correction and the relationship to demyelination determined by luxol blue histopathology. 2) Immunocytochemical analyses of brain tissue to determine if complement, leukocytes and the C5b-9 complex membrane attack may contribute to demyelination. 3) in vivo h-NMR arterial spin tagging or 14C-IAP measurement of cerebral perfusion to determine the effect of correction on global and regional cerebral perfusion and identification of mediators responsible for alterations in perfusion. 4) Determining whether prevention of perfusion changes will affect the threshold for BBB disruption measured by NMR determination of gadolinium-DTPA leakage into brain. 5) Examining whether increased osmolality alters cerebral energy metabolism by measuring 14C-2DG uptake and using 31P-NMR spectroscopy to measure bioenergetics. 6) Determining the effect of alterations in BBB permeability, cerebral perfusion, cerebral energy metabolism and complement activation on the development of neurologic dysfunction and demyelination. These experiments should identify the mechanisms by which correction of hyponatremia causes demyelination and should provide a model for studying other demyelinating diseases such as MS and other CNS diseases such as head trauma and AIDS, each of which exhibits BBB disruption.

描述：（改编自申请人的摘要）快速校正 低钠血症是一种常见的医疗状况，可能导致蓬蒂因和外the骨外血症 动物和人类的脱髓鞘。 最近的报道表明快速 血浆钠和渗透压的增加破坏了血脑屏障 （BBB）在低血浆渗透压值的慢性低钠大鼠比 在急性低钠患者或临床血症控制大鼠中；那快速 血浆钠的增加显着增加了脑灌注；那 慢性快速纠正后发生的BBB破坏 低钠血症之前，似乎与 脱髓鞘。 因此，总体研究目标是确定 BBB渗透性和脑灌注的这些改变与 随后发展神经系统症状和脱髓鞘 遵循慢性低钠血症的快速纠正。 实验将使用 稳定的CHN大鼠模型在快速纠正低钠血症后会产生 50-60％的大鼠脱髓鞘。 未纠正的CHN大鼠将作为 控件。 研究将包括：1）大脑的免疫细胞化学分析 IgG和白蛋白确定BBB渗透性何时何地增加 在更正和与卢克索确定的脱髓鞘的关系 蓝色组织病理学。 2）脑组织的免疫细胞化学分析 确定是否补体，白细胞和C5B-9复合膜攻击 可能有助于脱髓鞘。 3）体内H-NMR动脉自旋标记或 14C-IAP测量大脑灌注以确定 对全球和区域脑灌注的校正以及对 负责灌注改变的介体。 4）确定是否 预防灌注变化将影响BBB破坏的阈值 通过NMR测定Gadolinium-DTPA泄漏到大脑中的测量。 5） 检查渗透压增加是否通过改变脑能量代谢 测量14C-2DG摄取并使用31p-NMR光谱测量 生物能学。 6）确定BBB改变的影响 渗透性，脑灌注，脑能量代谢和补体 激活神经功能障碍和脱髓鞘。 这些实验应确定校正的机制 低钠血症会引起脱髓鞘，并应提供研究模型 其他脱髓鞘疾病，例如MS和其他中枢神经系统疾病，例如头部 创伤和艾滋病，每种艾滋病都会呈现BBB的破坏。