CPP‐115, a vigabatrin analogue, decreases spasms in the multiple‐hit rat model of infantile spasms

• Published in: Epilepsia (Copenhagen) Vol. 55; no. 1; pp. 94 - 102
• Main Authors: Briggs, Stephen W., Mowrey, Wenzhu, Hall, Charles B., Galanopoulou, Aristea S.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2014
• Subjects: 4-Aminobutyrate transaminase; Animals; Animals, Newborn; Anticonvulsants - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Epilepsy; GABA aminotransferase; Humans; Infant; Learning; Lipopolysaccharide; Male; Maze Learning - drug effects; Memory; Monitoring, Physiologic; Neurodevelopmental reflexes; Proline - analogs & derivatives; Proline - therapeutic use; Rats; Seizure; Spasms, Infantile - drug therapy; Learning; Epilepsy; GABA aminotransferase; Memory; Lipopolysaccharide; Neurodevelopmental reflexes; Seizure; Doxorubicin
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.12424

Summary Objective Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a γ‐aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP‐115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP‐115 in reducing spasms and its tolerability in the multiple‐hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated. Methods Male rats were treated with the protocol of the multiple‐hit model of IS on postnatal day 3 (PN3). Using a randomized, blinded, vehicle‐controlled, dose‐response study design, CPP‐115 (0.1, 1, or 5 mg/kg intraperitoneally [i.p.]) or vehicle was given daily (PN4–12) or as a single injection (PN7) after spasm onset. Intermittent video‐ or video‐electroencephalography (EEG) monitoring was done. Secondary end points included the following: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3–20), horizontal bar (PN13–20), and Barnes maze (PN16–19). Statistics used a linear mixed model of raw or normalized log‐transformed data, taking into account the repeated observations on each animal. Results The lower CPP‐115 doses (0.1–1 mg/kg/day, PN4–12) reduced spasms between PN6 and 7 without increasing mortality. CPP‐115 at 5 mg/kg/day (PN4–12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP‐115 injection (1 mg/kg, i.p.) decreased electroclinical spasms acutely but transiently. CPP‐115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasm cessation. CPP‐115 did not alter neurodevelopmental outcomes or visuospatial learning. Significance We provide proof‐of‐concept evidence that CPP‐115, a vigabatrin analogue, decreases spasms in the multiple‐hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP‐115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.