REGULATION OF EXTRACELLULAR SPACE IN EPILEPTOGENESIS

描述：(申请人摘要)细胞外间隙(ECS)的变化 已经在各种神经病理学的背景下进行了研究， 尤其是与头部受伤有关的。有些令人惊讶的是，ECS 在癫痫领域被相对忽视，即使有 有几项研究表明触觉相互作用的贡献 (即，流经细胞外空间的电流)增加兴奋性， 超同步性，癫痫发作蔓延。此外，实验表明， 细胞外渗透压的变化可以改变大脑的惊厥阈值。 最后，来自申请人实验室的最新研究表明， 常用的利尿剂，速尿，在测试中是抗惊厥药 体外和体内模型的数量。申请者提议考试 ECS的调节可能影响组织的潜在机制 兴奋性和致癫性。申请者将：1)测试多个 在癫痫发作和状态的完整动物模型中调节ECS的药物 癫痫；2)测量神经元和神经胶质肿胀以及相关的变化 海马片癫痫样活动期间的ECS；3)治疗 “癫痫”切片与改变ECS的药物，并关联药物的效果 ECS(和细胞肿胀)及其抗癫痫作用；4)研究 电池属性的变化(电压依赖电流、 细胞内钙)，当组织暴露于导致细胞 肿胀。 这些研究将构成一个初步的综合尝试，以检查 细胞肿胀(和内皮细胞的变化)与癫痫样活动的关系。 这样的方法可能会为开发新的 抗癫痫药物--可能特别有用的处理方法 在医学上难以治愈的癫痫发作以及预防性治疗中 “处于危险”的头部损伤患者。

DESCRIPTION: (Applicant's abstract) Changes in extracellular space (ECS) have been studied within the context of a variety of neuropathologies, particularly those associated with head injury. Somewhat surprisingly, ECS has been relatively neglected within the epilepsy field, even though there are several studies that suggest contributions of ephaptic interactions (i.e., current flow through extracellular space) to increased excitability, hyper-synchrony, and seizure spread. Further, experiments have shown that changes in extracellular osmolality can modify brain seizure threshold. Finally, recent studies from the applicant's laboratory have shown that a commonly used diuretic, furosemide, is "anticonvulsant" in tests against a number of in vitro and in vivo models. The applicant proposes to examine potential mechanisms by which modulation of ECS may affect tissue excitability and epileptogenicity. The applicant will: 1) test a number of agents that modulate ECS in intact animal models of seizure and status epilepticus; 2) measure neuronal and glial swelling, and related changes in ECS, during epileptiform activity in hippocampal slices; 3) treat "epileptic" slices with agents that alter ECS, and correlate drug effects of ECS (and cell swelling) with their anti-epileptic actions; and 4) study changes in cell properties (voltage-dependent currents, changes in intracellular calcium) when tissue is exposed to agents that cause cell swelling. These studies will constitute an initial integrated attempt to examine the relationship of cell swelling (and changes in ECS) to epileptiform activity. Such an approach may open unexplored avenues for the development of new anti-epileptic agents -- approaches that may be especially useful in dealing with medically-intractable seizures as well as in prophylactic treatment of "at risk" head injury patients.