Local distribution and toxicity of prolonged hippocampal infusion of muscimol
Local distribution and toxicity of prolonged hippocampal infusion of muscimol
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DOI：
10.3171/jns.2005.103.6.1035
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发表时间：
2005-12-01
影响因子：
4.1
通讯作者：
Oldfield, EH
中科院分区：
文献类型：
--
作者：
Heiss, JD;Walbridge, S;Oldfield, EH
Object.在内侧颞叶硬化症的复杂部分性癫痫发作患者中，主要抑制性神经递质γ-氨基丁酸（GABA）的活性在海马中降低。为了提供使用对流增强递送药物治疗复杂部分性癫痫发作的初步安全性和分布数据，并测试区域选择性神经元抑制的有效性和安全性，作者使用集成导管电极将蝇蕈醇（一种GABA-A受体激动剂）直接注入非人灵长类动物的海马体中。方法.将10只恒河猴分为三组：1）单独使用导管电极（四只猴）; 2）输注递增浓度的蝇蕈醇，然后输注媒介物（三只猴）;以及3）输注媒介物，然后输注与蝇蕈醇示踪剂混合的蝇蕈醇（三只猴）。在导管电极放置后5天开始输注，并持续5.6天，然后转换为其他药物。在输注前和输注期间获得头部磁共振（MR）图像和脑电图记录。进行脑组织学研究和定量放射自显影。神经功能正常的控制，当蝇蕈醇浓度为0.125 mM或更低，而更高的浓度（0.5和1 mM）产生可逆的冷漠和嗜睡。MR图像显示了液体分布，放射自显影显示了蝇蕈醇在整个海马和邻近白色物质中的分布。结论.靶向调节神经元活动是研究和治疗药物难治性癫痫的合理研究策略。
Object. The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the efficacy and safety of regional selective neuronal suppression, the authors infused muscimol, a GABA-A receptor agonist, directly into the hippocampus of nonhuman primates using an integrated catheter electrode. Methods. Ten rhesus monkeys were divided into three groups: 1) use of catheter electrode alone (four monkeys); 2) infusion of escalating concentrations of muscimol followed by vehicle (three monkeys); and 3) infusion of vehicle and subsequent muscimol mixed with muscimol tracer (three monkeys). Infusions were begun 5 days after catheter electrode placement and continued for 5.6 days before switching to the other agent. Head magnetic resonance (MR) images and electroencephalography recordings were obtained before and during the infusions. Brain histological studies and quantitative autoradiography were performed. Neurological function was normal in controls and when muscimol concentrations were 0.125 mM or less, whereas higher concentrations (0.5 and 1 mM) produced reversible apathy and somnolence. Fluid distribution was demonstrated on MR images and muscimol distribution was demonstrated on autoradiographs throughout the hippocampus and adjacent white matter. Conclusions. Targeted modulation of neuronal activity is a reasonable research strategy for the investigation and treatment of medically intractable epilepsy.