Glutamate Receptors in Epileptogenesis

描述(由申请人提供)：N-甲基-D-天冬氨酸受体(NMDAR)过度激活被认为是导致各种神经疾病的病理生理学的原因。这种参与导致了NMDAR拮抗剂的开发，用于治疗应用。事实证明，高亲和力的竞争性和非竞争性NMDAR拮抗剂由于不良反应突出，不适合人类使用。高亲和力的竞争性拮抗剂也能促进实验系统中突触的重组和谷氨酸受体的上调，这可能导致神经元回路异常和个体突触异常。中等亲和力、非竞争性和NR2B选择性的NMDAR拮抗剂引起的不良反应较少，仍然是可行的治疗选择。这些拮抗剂是否会改变神经元回路和单个突触，在很大程度上尚不清楚。NMDAR拮抗剂有望预防获得性癫痫。目前的治疗方法针对与完全发展的癫痫相关的癫痫发作，但不能预防脑损伤后获得的癫痫。癫痫发生是正常大脑变得容易慢性癫痫发作的过程，与电路重排和个别突触异常有关。因此，诱导突触重组和改变个体突触的NMDAR拮抗剂可能会加剧而不是抑制癫痫的发生。我们的目标是记录三类不同的NMDAR拮抗剂(NR2B选择性、高亲和力竞争性和中等亲和力非竞争性)对癫痫发生的影响，并确定不同类别的NMDAR拮抗剂对癫痫发生的影响是否与突触可塑性的变化有关。这些目标将在癫痫发生的大鼠海马片培养模型中使用药理学、电生理学、组织学和组织化学方法的组合来实现。这项研究的结果将提供关于使用不同类别的NMDAR拮抗剂进行慢性治疗的好处和潜在缺点的新信息。这些数据还将有助于更好地理解突触可塑性在癫痫发生中的作用。这一信息对于开发旨在预防获得性癫痫的治疗方法提供了合理的基础。

DESCRIPTION (provided by applicant): Excessive N-methyl-D-aspartate receptor (NMDAR) activation is thought to contribute to pathophysiology in a variety of neurological disorders. This involvement led to the development of NMDAR antagonists for therapeutic applications. High-affinity competitive and noncompetitive NMDAR antagonists proved unsuitable for human use due to prominent adverse effects. High-affinity, competitive antagonists also can promote synaptic reorganization and glutamate receptor up-regulation in experimental systems, which may lead to anomalous neuronal circuits and individual synapse abnormalities. Moderate-affinity noncompetitive and NR2B-selective NMDAR antagonists elicit fewer adverse effects and remain viable therapeutic options. Whether these antagonists alter neuronal circuits and individual synapses remains largely unexplored. NMDAR antagonists hold promise to prevent acquired epilepsy. Current therapies target seizures associated with fully developed epilepsy, but cannot prevent epilepsy acquired following brain insult. Epileptogenesis, the process by which a normal brain becomes prone to chronic seizures, is associated with circuitry rearrangements and individual synapse abnormalities. Thus, NMDAR antagonists that induce synaptic reorganization and alter individual synapses may exacerbate rather than inhibit epileptogenesis. Our goal for the proposed study is to document the effects of three distinct classes of NMDAR antagonists (NR2B-selective, high-affinity competitive and moderate-affinity uncompetitive) on epileptogenesis and to determine whether the effects of different classes of NMDAR antagonists on epileptogenesis are associated with alterations in synaptic plasticity. These aims will be accomplished using a combination of pharmacological, electrophysiological, histological and histochemical approaches in a rat hippocampal slice culture model of epileptogenesis. Results from this study will provide new information about the benefits and potential drawbacks of chronic treatment with different classes of NMDAR antagonists. These data also will lead to a greater understanding of the role of synaptic plasticity in epileptogenesis. This information is crucial in providing a rational basis for development of therapies designed to prevent acquired epilepsy.