ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability

Abstract

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.

Fig. 1

Neuroendocrine (A) and limbic (B) stress-activated corticotropin-releasing hormone (CRH) loops. (A) Stress-conveying signals rapidly activate immediate early genes in CRH expressing neurons of the central nucleus of the amygdala (ACe). Rapid CRH release in the ACe activates CRH expression in the hypothalamic paraventricular nucleus (PVN) to secrete CRH into the hypothalamo-pituitary portal system, inducing ACTH and glucocorticoid secretion from the pituitary and adrenal, respectively. Glucocorticoids exert a negative feedback on the PVN (directly and via the hippocampus), yet activate CRH gene expression in the amygdala, potentially promoting further CRH release in this region. (B) CRH-expressing GABAergic interneurons (small round cells) in the principal cell layers of the hippocampal CA1, CA3, and the dentate gyrus (DG) are positioned to control excitability of the pyramidal and granule cells, respectively. These neurons may be influenced by the stress-evoked release of CRH from the ACe via connections in the entorhinal cortex. Dark and light arrows denote established or putative potentiating and inhibitory actions, respectively. Arrows do not imply monosynaptic connections.