ACTH: a structure-activity study on pilocarpine-induced epilepsy.
Intracerebroventricularly applied pilocarpine (2.4 mg/2 microliters) immediately produced symptoms of epilepsy, ranging from akinesia to motor seizures, in rats. Whereas ACTH-(1-39), ACTH-(1-24), ACTH-(1-18), ACTH-(1-16) and ACTH-(18-39) were not active, subcutaneous pretreatment with smaller ACTH-like fragments, such as ACTH-(4-9), ACTH-(4-10), ACTH-(4-10)(7D-Phe), ACTH-(7-16), and Org2766, reduced the severity of the epilepsy. Moreover, fewer rats developed motor seizures. Thus, ACTH fragments devoid of peripheral endocrine activity reduce pilocarpine-induced epileptiform activity in rats. A narrow bell-shaped dose-response relationship was found. Except for ACTH-(7-16), which was active in a dose of 1 and 10 micrograms/rat s.c., the other fragments were only active at one dose (10 micrograms/rat). The anti-epileptic properties appeared to reside in the sequence 1-16, and more specifically in the sequences 4-7 and 7-16, of the ACTH molecule.
Croiset
G
G
Rudolf Magnus Institute, Department of Pharmacology, Medical Faculty, University of Utrecht, Netherlands.
De Wied
D
D
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D010446:Peptide Fragments; D010862:Pilocarpine; C013765:Org 2766; D000324:Adrenocorticotropic Hormone