Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy.
Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy.
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DOI：
10.1523/jneurosci.4852-10.2011
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发表时间：
2011-02-09
期刊：
影响因子：
--
通讯作者：
Lew FH
中科院分区：
文献类型：
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作者：
Buckmaster PS;Lew FH
颞叶癫痫很常见，很难有效治疗。颗粒细胞轴突(苔藓纤维)出芽是内侧颞叶癫痫患者常见的神经病理改变，但其在癫痫发生中的作用尚不清楚且存在争议。局部或全身注射雷帕霉素可抑制mTOR信号通路，并抑制苔藓纤维的萌发。我们测试了在匹罗卡品诱导的小鼠癫痫持续状态后的一天开始，长期的雷帕霉素系统治疗是否会抑制苔藓纤维的萌发，并影响自发癫痫的发展。经历了癫痫持续状态，然后用雷帕霉素治疗2个月的小鼠，苔藓纤维发芽明显减少(42%的赋形剂治疗的动物)，而且效果与剂量有关。然而，行为和视频/EEG监测显示，雷帕霉素和赋形剂治疗的小鼠表现出类似频率的自发癫痫发作。这些发现表明，苔藓纤维发芽既不利于也不抗惊厥；然而，有一些警告。雷帕霉素治疗也减少了癫痫相关齿状回的肥大，但对颗粒细胞的增殖、肺门神经元的丢失或异位颗粒细胞的产生没有显著影响。这些发现与肺门神经元丢失和异位颗粒细胞可能参与颞叶癫痫发生的假说相一致。
Temporal lobe epilepsy is prevalent and can be difficult to treat effectively. Granule cell axon (mossy fiber) sprouting is a common neuropathological finding in patients with mesial temporal lobe epilepsy, but its role in epileptogenesis is unclear and controversial. Focally infused or systemic rapamycin inhibits the mTOR signaling pathway and suppresses mossy fiber sprouting in rats. We tested whether long-term systemic treatment with rapamycin, beginning one day after pilocarpine-induced status epilepticus in mice, would suppress mossy fiber sprouting and affect the development of spontaneous seizures. Mice that had experienced status epilepticus and then were treated for 2 months with rapamycin displayed significantly less mossy fiber sprouting (42% of vehicle-treated animals), and the effect was dose dependent. However, behavioral and video/EEG monitoring revealed that rapamycin- and vehicle-treated mice displayed spontaneous seizures at similar frequencies. These findings suggest mossy fiber sprouting is neither pro- nor anti-convulsant; however, there are caveats. Rapamycin treatment also reduced epilepsy-related hypertrophy of the dentate gyrus but did not significantly affect granule cell proliferation, hilar neuron loss, or generation of ectopic granule cells. These findings are consistent with the hypotheses that hilar neuron loss and ectopic granule cells might contribute to temporal lobe epileptogenesis.