How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis
How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis
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DOI：
10.1016/s0387-7604(01)00312-6
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发表时间：
2001-11-01
影响因子：
1.7
通讯作者：
Baram, TZ
中科院分区：
文献类型：
--
作者：
Brunson, KL;Eghbal-Ahmadi, M;Baram, TZ
West综合征（WS）与多种病因有关。这一事实表明，这些病因必须有一个“最终的共同途径”，它只在婴儿期的成熟状态下作用于未成熟的大脑，导致WS。任何关于WS发病机制的理论都必须解释这种疾病的独特特征。例如，一个实体怎么可能有这么多病因？为什么WS只在婴儿期出现，即使在产前发生了已知的侮辱，为什么它消失了？为什么WS与持久的认知功能障碍有关？而且，重要的是，为什么这些癫痫发作-不像大多数其他-对激素，ACTH的治疗反应？ACTH在人体生理学中的既定激素作用是在对所有应激刺激（包括对大脑的损伤）的反应的神经内分泌级联中起作用。作为该功能的一部分，已知ACTH抑制促肾上腺皮质激素释放激素（CRH）的产生，所述促肾上腺皮质激素释放激素（CRH）是响应于不同的损伤和应激源而产生的肽。WS的许多病因都导致应激反应的激活，包括应激神经激素CRH的产生和分泌增加。在婴儿动物模型中，CRH已被证明会导致严重的癫痫发作和与学习和记忆有关的区域的神经元死亡。CRH的这些作用仅限于婴儿期，因为介导其对神经元作用的CRH受体在该发育期最丰富。已知ACTH给药通过负反馈机制抑制CRH的产生和释放。因此，ACTH对WS的疗效可能取决于其降低促排尿应激神经激素CRH水平的能力。WS病理生理学的CRH过量理论不仅与ACTH效应的特征一致，而且与WS的许多不同“原因”一致，与受影响婴儿脑脊液中的异常ACTH水平一致，与癫痫发作的自发消失一致。此外，如果CRH是癫痫发作的原因，并且CRH介导的神经元损伤导致WS患者的认知结果恶化，则阻断CRH对其受体的作用的药物可能为这种疾病提供更好的治疗。(C)出版社：Elsevier Science B. V.
West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a 'final common pathway' for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures - unlike most others - respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and with the spontaneous disappearance of the seizures. Furthermore, if CRH is responsible for the seizures, and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of individuals with WS, then drugs which block the actions of CRH on its receptors may provide a better therapy for this disorder. (C) 2001 Published by Elsevier Science B.V.