Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists.
OBJECTIVE
Infantile spasms (IS) are an age-specific seizure disorder occurring in 1:2,000 infants and associated with mental retardation in approximately 90% of affected individuals. The costs of IS in terms of loss of lifetime productivity and emotional and financial burdens on families are enormous. It is generally agreed that the seizures associated with IS respond poorly to most conventional anticonvulsants. In addition, in the majority of patients, a treatment course with high-dose corticotropin (ACTH) arrests the seizures completely within days, often without recurrence on discontinuation of the hormone. However, the severe side effects of ACTH require development of better treatments for IS. Based on the rapid, all-or-none and irreversible effects of ACTH and on the established physiological actions of this hormone, it was hypothesized that ACTH eliminated IS via an established neuroendocrine feedback mechanism involving suppression of the age-specific endogenous convulsant neuropeptide corticotropin-releasing hormone (CRH). Indeed, IS typically occur in the setting of injury or insult that activate the CNS stress system, of which CRH is a major component. CRH levels may be elevated in the IS brain, and the neuropeptide is known to cause seizures in infant rats, as well as neuronal death in brain regions involved in learning and memory. If 'excess' CRH is involved in the pathogenesis of IS, then blocking CRH receptors should eliminate both seizures and the excitotoxicity of CRH-receptor-rich neurons subserving learning and memory.


METHODS
With FDA approval, alpha-helical CRH, a competitive antagonist of the peptide, was given as a phase I trial to 6 infants with IS who have either failed conventional treatment or who have suffered a recurrence. The study was performed at the Clinical Research Center of the Childrens Hospital, Los Angeles. The effects of alpha-helical CRH on autonomic parameters (blood pressure, pulse, temperature, respiration) were determined. In addition, immediate and short-term effects on ACTH and cortisol and on electrolytes and glucose were examined. The potential efficacy of alpha-helical CRH for IS was studied, using clinical diaries and video EEG.


RESULTS
alpha-Helical CRH, a peptide, did not alter autonomic or biochemical parameters. Blocking peripheral CRH receptors was evident from a transient reduction in plasma ACTH and cortisol. No evidence for the compound's penetration of the blood-brain barrier was found, since no central effects on arousal, activity or seizures and EEG patterns were observed. In addition, a striking resistance of the patients' plasma ACTH to the second infusion of alpha-helical CRH was noted.


CONCLUSIONS
Peptide analogs of CRH do not cross the blood-brain barrier, and their effects on peripheral stress hormones are transient and benign. Nonpeptide compouds that reach CNS receptors are required to test the hypothesis that blocking CRH receptors may ameliorate IS and its cognitive consequences.
Baram
T Z
TZ
Department of Anatomy/Neurobiology, University of California at Irvine, CA 92697-4475, USA. tallie@uci.edu
Mitchell
W G
WG
Brunson
K
K
Haden
E
E
D000324:Adrenocorticotropic Hormone / Q000097:blood; D001341:Autonomic Nervous System / Q000187:drug effects; D002675:Child, Preschool; D003346:Corticotropin-Releasing Hormone / Q000627:therapeutic use*; D005260:Female; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007223:Infant; D008297:Male; D008959:Models, Neurological; D010865:Pilot Projects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013036:Spasms, Infantile / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D006727:Hormone Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; C069206:alpha helical corticotropin-releasing hormone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone