Hernández-Sánchez C, Basile A S, Fedorova I, Arima H, Stannard B, Fernandez A M, Ito Y, LeRoith D
Section on Molecular and Cellular Physiology, Clinical Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3549-54. doi: 10.1073/pnas.051012898. Epub 2001 Feb 27.
The ability of the sulfonylurea receptor (SUR) 1 to suppress seizures and excitotoxic neuron damage was assessed in mice transgenically overexpressing this receptor. Fertilized eggs from FVB mice were injected with a construct containing SUR cDNA and a calcium-calmodulin kinase IIalpha promoter. The resulting mice showed normal gross anatomy, brain morphology and histology, and locomotor and cognitive behavior. However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [(3)H]glibenclamide binding to the cortex, hippocampus, and striatum. These mice resisted kainic acid-induced seizures, showing a 36% decrease in average maximum seizure intensity and a 75% survival rate at a dose that killed 53% of the wild-type mice. Kainic acid-treated transgenic mice showed no significant loss of hippocampal pyramidal neurons or expression of heat shock protein 70, whereas wild-type mice lost 68-79% of pyramidal neurons in the CA1-3 subfields and expressed high levels of heat shock protein 70 after kainate administration. These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function.
在转基因过度表达磺脲类受体（SUR）1的小鼠中评估了该受体抑制癫痫发作和兴奋性毒性神经元损伤的能力。将含有SUR cDNA和钙调蛋白激酶IIα启动子的构建体注射到FVB小鼠的受精卵中。所得到的小鼠表现出正常的大体解剖结构、脑形态和组织学，以及运动和认知行为。然而，它们过度表达SUR1转基因，导致与皮质、海马和纹状体结合的[³H]格列本脲密度增加9至12倍。这些小鼠抵抗 kainic 酸诱导的癫痫发作，在杀死53%野生型小鼠的剂量下，平均最大癫痫发作强度降低36%，存活率为75%。经 kainic 酸处理的转基因小鼠海马锥体细胞无明显损失，热休克蛋白70也无明显表达，而野生型小鼠在给予 kainate 后，CA1-3亚区68-79%的锥体细胞丢失，热休克蛋白70表达水平较高。这些结果表明，仅在前脑结构中转基因过度表达SUR1可显著保护小鼠免受癫痫发作和神经元损伤，而不干扰运动或认知功能。
