Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease
Fig 5
Allopregnanolone (Allo) dose-response comparison by subcutaneous (SC), intramuscular (IM), and intravenous (IV) routes of administration.
Ovariectomized female rats (left panel) were compared to age-matched male rats (right panel) following SC (A. and B.), IM (C. and D.), or IV (E. and F.) bolus injection and challenged with a motor coordination behavioral task to assess level of sedation at timed intervals until recovery. SC/IM formulation: 6 mg/ml Allo solution in 0.9% sodium chloride with 24% sulfobutyl ether β-cyclodextrin sodium (SBECD). IV formulation: 1.5 mg/ml Allo solution in 0.9% sodium chloride with 6% SBECD. The volume of vehicle administered was equal to the volume administered with the highest dose, i.e. 8 mg/kg (SC/IM) or 2 mg/kg (IV). Balance Beam Behavioral Scoring System: 4 = reach platform; 3 = takes steps; 2 = all paws on top; 1 = clasp; 0 = fall. n = 4, interval points represent mean value ± SEM. Area bound by sedation curve as an indicator of rapid Allo target engagement. G. The area bound by the sedation curve (above the curve; Fig 5A–5F) (AUCsed) was calculated to determine the sedative component of GABAA receptor activation in the brain as an indicator of Allo delivery. AUCsed was calculated and expressed as behavioral score (a score between 4 and 0) multiplied by minutes post-treatment. Sex differences in the Allo-induced sedation response were determined. * p<0.05, ** p<0.01, n = 4, bars represent mean value ± SEM.