Effects of distinct classes of N-methyl-D-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro:: suppression by NR2B-selective antagonists
Effects of distinct classes of N-methyl-D-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro:: suppression by NR2B-selective antagonists
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DOI：
10.1016/j.neuropharm.2004.07.036
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发表时间：
2004-12-01
影响因子：
4.7
通讯作者：
Bausch, SB
中科院分区：
文献类型：
--
作者：
Wang, XM;Bausch, SB
用高亲和力、竞争性N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂长期治疗可促进轴突发芽，诱导神经元丢失并加重与颞叶癫痫相关的癫痫发作。中等亲和力的非竞争性和NR 2B亚基选择性NMDAR拮抗剂是否引起类似的反应仍然在很大程度上未被探索。我们直接比较了不同类别的NMDAR拮抗剂对电描记癫痫发作，轴突发芽和神经元存活的影响，在海马切片培养物中使用电生理记录和组织学，这些海马切片培养物用载体，D-APV（高亲和力竞争性），Ro 25-6981或艾芬地尔（NR 2B选择性）或美金刚（中等亲和力非竞争性）长期处理。颗粒细胞层场电位记录显示，GABA（A）受体阻断后，溶媒处理的培养物中出现多次自发性电图癫痫发作。与媒介物相比，在用NR 2B选择性拮抗剂处理的培养物中癫痫发作显著减少，并且在用中等亲和力非竞争性或高亲和力竞争性拮抗剂处理的培养物中癫痫发作略微增加。一般来说，与媒介物相比，用NR 2B选择性拮抗剂处理的培养物表现出较少的颗粒细胞苔藓纤维轴突（MFS）发芽和更多的颗粒细胞层神经元。用高亲和力竞争性或模式速率亲和力非竞争性NMDAR拮抗剂处理的培养物显示MFS增加和颗粒细胞层神经元减少。这些数据揭示了不同类别的NMDAR拮抗剂对癫痫发作表达、轴突发芽和神经元存活的不同影响，并表明这些反应之间存在关联。爱思唯尔有限公司出版
Chronic treatment with high-affinity, competitive N-methyl-D-aspartate receptor (NMDAR) antagonists can promote axonal sprouting, induce neuronal loss and exacerbate seizures associated with temporal lobe epilepsy. Whether moderate-affinity uncompetitive and NR2B subunit-selective NMDAR antagonists elicit similar responses remains largely unexplored. We directly compared the effects of distinct classes of NMDAR antagonists on electrographic seizures, axonal sprouting and neuronal survival using electrophysiological recordings and histology in hippocampal slice cultures treated chronically with vehicle, D-APV (high-affinity competitive), Ro 25-6981 or ifenprodil (NR2B-selective), or memantine (moderate-affinity uncompetitive). Granule cell layer field potential recordings revealed multiple spontaneous electrographic seizures in vehicle-treated cultures following GABA(A) receptor blockade. Compared to vehicle, seizures were dramatically reduced in cultures treated with NR2B selective antagonists and slightly increased in cultures treated with moderate-affinity uncompetitive or high-affinity competitive antagonists. In general, compared to vehicle, cultures treated with NR2B selective antagonists exhibited less sprouting of granule cell mossy fiber axons (MFS) and more granule cell layer neurons. Cultures treated with high-affinity competitive or mode rate-affinity uncompetitive NMDAR antagonists showed increased MFS and fewer granule cell layer neurons. These data reveal differential effects of distinct classes of NMDAR antagonists on seizure expression, axonal sprouting and neuronal survival and suggest an association between these responses. Published by Elsevier Ltd.