SCH-50911 is a reversal agent for 1,4-BD and GBL toxicity

Background: 1,4-BD and GBL produce toxicity through their common metabolite, GHB, which interacts with GHB and [GABA.sub.B] receptors. Objective: We investigated if 1,4-BD and GBL neurotoxicity can be decreased with SCH-50911, a high affinity selective [GABA.sub.B] receptor antagonist. Methods: For 1,4-BD, 16 male CD-1 mice received 1,4-BD 600 mg/kg i.p. followed 15 minutes later by SCH-50911 30 mg/kg i.p. (N = 8) or control injection (N = 8). For GBL, 16 mice received GBL 750 mg/kg i.p. followed 15 minutes later by SCH-50911 30 mg/kg i.p. (N = 8) or control injection (N = 8). Mice from all groups were then evaluated for neurotoxicity every 15 minutes by the righting reflex (RR), rotarod test (RT), grip strength (GS, peak pull force in lbs.), and open field locomotion (OFL, distance traveled in cm.). Results: 1,4-BD and GBL produced initial deficits for all outcome measures in all mice. SCH-50911 decreased the duration of RR failure for 1,4-BD and GBL from 135 and 180 min., respectively, in controls to 45 min. in treated mice. SCH-50911 decreased the duration of RT failure for 1,4-BD and GBL from 210 and 420 min. in controls to 105 and 90 min. in treated mice, respectively. SCH-50911 promoted more rapid recovery of GS to baseline values versus controls for both 1,4-BD and GBL (P < 0.05 by area-under-the-curve, AUC, analysis). For OFL, SCH-50911 significantly improved the distance traveled by treated mice versus controls (P < 0.05 by AUC analysis) for GBL only. Conclusion: SCH-50911 significantly reverses neurotoxicity related to 1,4-BD and GBL, presumably by antagonizing GHB effects at the [GABA.sub.B] receptor.
Quang L, Desai M, Maher T, Woolf A, Shannon M. Children's Hospital Boston/Harvard Medical School, Massachusetts College of Pharmacy and Health Sciences, Boston, [...]