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.