Brunson K L, Avishai-Eliner S, Baram T Z
Departments of Pediatrics, Anatomy and Neurobiology, and Neurology, University of California, Irvine, Irvine, California 92697, USA.
Int Rev Neurobiol. 2002;49:185-97. doi: 10.1016/s0074-7742(02)49013-7.
The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies. However, the mechanisms for this efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors. The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH--compared with steroids--for this disorder are the focus of this chapter. First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed. This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain. This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions. Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH. Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented. This downregulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS.
在前瞻性对照研究中已证实促肾上腺皮质激素（ACTH），尤其是高剂量时，对快速且完全消除婴儿痉挛症（IS）具有疗效。然而，这种疗效的机制仍不清楚。ACTH可促进肾上腺类固醇（糖皮质激素）的释放，大多数ACTH对中枢神经系统的作用都归因于糖皮质激素受体的激活。本章重点关注这些受体的激活改善婴儿痉挛症的方式以及与类固醇相比，ACTH对该疾病增强治疗效果的基础。首先，提出了一种可能的“共同兴奋性通路”，它与婴儿痉挛症的多种病因相符，并解释了该疾病为何局限于婴儿期。这一观点基于所有引发婴儿痉挛症的因素都会激活大脑的天然“应激系统”这一事实。这涉及边缘系统中易于发作癫痫的脑区应激激活神经肽促肾上腺皮质激素释放激素（CRH）的合成和释放增加。CRH在发育中的实验动物中会引发严重癫痫发作以及边缘神经元损伤。作为治疗给予的类固醇或在用ACTH治疗时从肾上腺分泌的类固醇，会减少某些脑区CRH的产生和释放。其次，考虑了ACTH通过最近鉴定的黑皮质素受体直接影响边缘神经元的假说，重点关注ACTH对CRH表达的影响。展示了实验数据，表明ACTH能有效降低杏仁核神经元中CRH的表达。这种下调在通过实验消除类固醇或阻断其受体时并未消除，并且可由不促进类固醇释放的中枢给予的ACTH片段重现。重要的是，选择性阻断黑皮质素受体可防止ACTH诱导的CRH表达下调，为这些受体参与ACTH发挥此作用的机制提供了直接证据。因此，ACTH可能通过两种作用机制降低婴儿痉挛症中的神经元兴奋性：（1）通过诱导类固醇释放；（2）通过对黑皮质素受体的直接、不依赖类固醇的作用。这些联合作用可能解释了ACTH在婴儿痉挛症治疗中已确立的强大临床效果。
