ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures.
ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures.
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DOI：
10.3389/fneur.2016.00065
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发表时间：
2016
影响因子：
3.4
通讯作者：
Hernan AE
中科院分区：
文献类型：
--
作者：
Massey AT;Lerner DK;Holmes GL;Scott RC;Hernan AE
早期癫痫发作（ELS）通常与认知和精神共病有关，对生活质量有害。在ELS大鼠模型中，我们探索了成年大鼠的长期认知结果。使用ACTH，一种内源性HPA轴激素给予严重癫痫儿童，我们试图防止认知缺陷。通过与地塞米松的比较，我们试图将ACTH的皮质类固醇效应与其他潜在的作用机制分离开来。尽管有ELS病史的大鼠能够获得条件性恐惧学习范式和对照，但这些大鼠消除恐惧记忆的能力存在显著缺陷。促肾上腺皮质激素治疗没有改变任何癫痫发作参数，但仍然能够显着改善这种恐惧消退，而地塞米松治疗在同一时期没有。这种促肾上腺皮质激素的影响是特定的恐惧灭绝赤字，而不是空间学习缺陷的水迷宫。此外，促肾上腺皮质激素没有改变癫痫发作的潜伏期或持续时间，这表明认知和癫痫发作的结果可能是分离的。黑皮质素受体的表达水平，结合促肾上腺皮质激素，被发现是显着低于动物经历了ELS比在对照组动物，可能涉及中央黑皮质素受体失调的ELS的影响，并提出了促肾上腺皮质激素的作用机制。综上所述，这些数据表明，早期治疗与ACTH可以有显着的长期后果的认知ELS的历史独立的癫痫发作停止的动物，并可能通过中枢神经系统黑皮质素受体通路的一部分。
Early life seizures (ELS) are often associated with cognitive and psychiatric comorbidities that are detrimental to quality of life. In a rat model of ELS, we explored long-term cognitive outcomes in adult rats. Using ACTH, an endogeneous HPA-axis hormone given to children with severe epilepsy, we sought to prevent cognitive deficits. Through comparisons with dexamethasone, we sought to dissociate the corticosteroid effects of ACTH from other potential mechanisms of action. Although rats with a history of ELS were able to acquire a conditioned fear learning paradigm and controls, these rats had significant deficits in their ability to extinguish fearful memories. ACTH treatment did not alter any seizure parameters but nevertheless was able to significantly improve this fear extinction, while dexamethasone treatment during the same period did not. This ACTH effect was specific for fear extinction deficits and not for spatial learning deficits in a water maze. Additionally, ACTH did not alter seizure latency or duration suggesting that cognitive and seizure outcomes may be dissociable. Expression levels of melanocortin receptors, which bind ACTH, were found to be significantly lower in animals that had experienced ELS than in control animals, potentially implicating central melanocortin receptor dysregulation in the effects of ELS, and suggesting a mechanism of action for ACTH. Taken together, these data suggest that early treatment with ACTH can have significant long-term consequences for cognition in animals with a history of ELS independently of seizure cessation and may act in part through a CNS melanocortin receptor pathway.