Acute and Chronic Administration of Repository Corticotropin Injection in Rats Stimulates Neurosteroid Synthesis
Abstract number :
3.265
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2021
Submission ID :
1825809
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Ashish Dhir, PhD - University of California, Davis, Sacramento, CA; Chun-Yi Wu, PhD - Assistant Project Scientist, Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA; Michael Rogawski, MD, PhD - Professor, Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA
Rationale: Repository corticotropin injection (RCI; Acthar® Gel), a complex mixture of ACTH analogs and other pituitary peptides in a depot formulation, is an accepted treatment for infantile spasms (IS). RCI stimulates endogenous glucocorticoid secretion, but there is evidence that it may be superior to exogenous glucocorticoids in the management of IS. We investigated the hypothesis that the superior efficacy could in part be due to stimulation by RCI of the synthesis of non-glucocorticoid neurosteroids that act as positive modulators of GABA-A receptors and have antiseizure properties. A study in rats exploring the effects of acute and chronic administration of RCI on the plasma levels of the neurosteroids tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO), and we also assessed the effects of RCI on seizure threshold in rats.
Methods: Adult male Sprague-Dawley rats underwent jugular vein cannulation 7-10 d before the study. To examine the acute effects of RCI, rats were injected subcutaneous (SC) with RCI (10, 50 and 100 IU/kg) or the corresponding vehicle or saline. Following dosing, blood was drawn from the jugular vein at time intervals between 0-300 min and in some cases up to 24 h. To study chronic treatment with RCI, a 50 IU/kg dose or saline was administered SC once daily in the morning for 7 d. On day 8 (24 h after the final injection on day 7), blood was collected at intervals up to 300 min. Blood was also collected for trough level measurements 24 h after each injection. Plasma was separated and THDOC and ALLO levels were estimated using LC/MS assay. In another cohort of animals dosed daily with RCI (50 IU/kg) or saline for 8 d, the timed IV PTZ seizure threshold test was administered 2 h after the final dose to assess antiseizure effects of the treatment.
Results: Acute treatment with RCI at 10, 50 and 100 IU/kg caused significant increases in THDOC (Cmax: 1237 ± 103; 1454 ± 178; 2307 ± 171 ρg/ml) and ALLO (Cmax: 1437 ± 314; 2946 ± 692; 3022 ± 452 ρg/ml) levels compared with vehicle (50 and 100 IU dose volume Eq: THDOC 575 ± 20 and 814 ± 149 ρg/ml; ALLO 343 ± 24 and 615 ± 171 ρg/ml, respectively). Levels remained elevated for 300 min after dosing. In chronic RCI treated rats, the rise in plasma THDOC day 8 occurred more rapidly and was larger (Cmax: RCI 4404 ± 481 vs saline 182 ± 27) than with acute treatment. Trough level measurements in the chronic dosing protocol indicated that neurosteroids levels returned to baseline between injections. RCI administration was not associated with a change in seizure threshold.
Conclusions: Acute RCI treatment caused a transitory increase in plasma THDOC and ALLO levels. The increase of THDOC was greater in animals that had received chronic dosing. The neurosteroid levels obtained with the dosing scheme used in this study were not associated with a change in seizure threshold. It remains to be determined whether RCI influences neurosteroid levels when used in the treatment of infantile spasms in humans and if any changes that occur contribute to therapeutic activity.
Funding: Please list any funding that was received in support of this abstract.: Mallinckrodt Pharmaceuticals Ltd., USA.
Anti-seizure Medications