NPY suppresses seizures and modulates thalamocortical activity in animal models of generalized epilepsy

癫痫是社区中最常见的严重慢性神经系统疾病，在一生中影响多达3%的人口，在任何时候影响0.5-1%的人口。失神性癫痫是最常见的癫痫类型之一，最常见于儿童和青少年时期，可能持续到成年。抗癫痫药物可有效控制大多数患者的失神发作，但有一个重要的群体（20-40%）患者的失神发作在目前的药物治疗下仍不受控制。最近，人们对大脑中的一种化学物质，如神经肽Y (NPY)，在癫痫中可能起的作用产生了相当大的兴趣。该研究计划将检验NPY在几种缺失性癫痫动物模型中的作用。我们最近在大鼠全面性癫痫遗传模型中发现NPY抑制癫痫发作，这似乎是由Y2受体介导的。这项工作将建立在这些新发现的基础上，并确定这种影响在大脑中的定位，以及潜在的机制。我们将在不同物种的几种模型中检查NPY的作用，一种是自发性癫痫发作的遗传大鼠模型，另一种是用化学物质诱导癫痫发作的小鼠模型。这将决定其广泛的适用性。我们还将确定去除NPY或NPY受体对NPY对癫痫表达的影响。最后，大脑记录技术将用于确定NPY保护作用的机制和大脑内的位置。该项目有可能为NPY在失神发作的表达和调节中的作用提供新的见解。NPY相关机制可能是开发一类新的治疗缺失性癫痫的药物的靶点。在失神发作表达中被确定为重要的靶标也可能被证明与其他类型的广泛性癫痫综合征相关。

Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime and 0.5-1% at any one time. Absence epilepsy is one of the most common types of epilepsy, most frequently seen in childhood and teenage years that may persist into adulthood. Anti-epileptic drugs are effective in controlling absence seizures in most patients, however there is an important group (20-40%) of patients in whom the absence seizures remain uncontrolled with current medications. Recently there has been considerable interest in the role that chemical in the brain, such as neuropeptide Y (NPY), may play in epilepsy. The research proposed will examine the role of NPY in several animal models of absence epilepsy. We have recently shown that NPY suppresses absence seizures in a rat genetic model of generalised epilepsy, and that this appears to be mediated by Y2 receptors. This work will build on these novel findings, and determine the localisation of the effect within the brain, and the underlying mechanism. We will check NPY effects across several models in different species, a genetic rat model with spontaneous seizures, and in mice treated with a chemical to induce seizures. This will determine its broad applicability. We will also determine the effects of removal of NPY or NPY receptors on the effects of NPY on seizure expression. Finally, brain recording techniques will be applied to determine the mechanism and site within the brain underlying the protective actions of NPY. The project has the potential to provide novel insights into the role of NPY in the expression and modulation of absence seizures. NPY related mechanisms might represent targets for the development of a new class of therapeutic agents for the treatment of absence epilepsy. Targets that are identified as being important in the expression of absence seizures may also prove to be relevant in other types of generalised epilepsy syndromes.