糖皮质激素受体特异性调节剂CORT108297可减轻癫痫持续状态后的脑部病变。
The glucocorticoid receptor specific modulator CORT108297 reduces brain pathology following status epilepticus.
作者信息
Wulsin Aynara C, Kraus Kimberly L, Gaitonde Kevin D, Suru Venkat, Arafa Salwa R, Packard Benjamin A, Herman James P, Danzer Steve C
机构信息
Cincinnati Children's Hospital Medical Center, Department of Anesthesia, USA; Cincinnati Children's Hospital Medical Center, Department of Pediatrics, USA; University of Cincinnati, Medical Scientist Training Program, USA; University of Cincinnati, Neuroscience Graduate Program, USA.
Cincinnati Children's Hospital Medical Center, Department of Anesthesia, USA; University of Cincinnati, Medical Scientist Training Program, USA; University of Cincinnati, Neuroscience Graduate Program, USA.
出版信息
Exp Neurol. 2021 Jul;341:113703. doi: 10.1016/j.expneurol.2021.113703. Epub 2021 Mar 18.
OBJECTIVE
Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297.
METHODS
Mice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress.
RESULTS
Treatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression.
INTERPRETATION
Results demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus.
目的
癫痫持续状态后糖皮质激素水平迅速升高，并在损伤后数周内持续升高。为了确定糖皮质激素受体激活是否导致癫痫持续状态的病理后遗症，用一种新型糖皮质激素受体调节剂C108297对小鼠进行治疗。
方法
在匹鲁卡品诱导的癫痫持续状态后一天开始，用C108297或赋形剂对小鼠治疗10天。评估基线和应激诱导的糖皮质激素分泌，以确定下丘脑-垂体-肾上腺轴的高反应性是否可以得到控制。通过量化海马异位颗粒细胞密度、小胶质细胞密度、星形胶质细胞密度和苔藓细胞丢失来评估癫痫持续状态诱导的病理学。通过确定束缚应激后Fos免疫反应性神经元的密度间接检查神经网络功能。
结果
用C108297治疗可减轻癫痫持续状态后皮质酮的分泌过多。治疗还降低了门区异位颗粒细胞的密度并减少了小胶质细胞增殖。另一方面，在接受治疗的小鼠中苔藓细胞丢失并未得到预防。C108297改变了Fos蛋白的细胞分布，但未恢复正常的表达模式。
解读
结果表明，C108297可使基线皮质酮水平正常化，并提示糖皮质激素信号传导与癫痫持续状态后结构变化的发生有关。这些发现支持进一步开发糖皮质激素受体调节剂作为预防癫痫持续状态后脑病理学的新型疗法。
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