The hypothesis that systemic or intraventricular administration of corticotropin (ACTH) acts directly on limbic neurons to modulate corticotropin-releasing hormone (CRH) gene expression, independently of adrenal stimulation, was tested and confirmed in experiments on developing rats (9-11 days postnatal) at the University of California, Irvine. This down-regulation of CRH gene expression was not abolished in adrenalectomized animals, and was prevented by selective blocking of melanocortin receptors. It was reproduced by an ACTH fragment that does not promote the release of steroids. The authors conclude that ACTH activates melanocortin receptors to modulate CRH gene expression in amygdala neurons, supporting a direct, steroid independent anticonvulsant action of ACTH. [1]
COMMENT. A direct, steroid independent mechanism of ACTH was postulated following clinical and laboratory animal studies in the 1950s and 60s, in Chicago at the Division of Neurology, Children’s Memorial Hospital, and at the University of Utah. Effects of ACTH on seizure thresholds varied with age, and were demonstrated in both intact and adrenalectomized animals (Woodbury, Timiras and Goodman, 1954, 1963; Millichap, Wasserman and Belton, 1957, 1965). Immature rats from birth to 8 days had a high seizure threshold. Between 8 and 16 days, brain excitability increased rapidly, and the threshold to experimental seizures was lowest at 25 to 30 days. Brunson and associates chose immature rats of 9-11 days for their experiments, at a time of relatively low seizure threshold, and equivalent to the age of infants with infantile spasms. ACTH may decrease this age-related excessive brain excitability by repressing CRH expression. Snead OC in an editorial describes this model of research as bedside-to-bench, and back. [2]