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

Abstract

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.

• Authors: Stephen W Briggs, Wenzhu Mowrey, Charles B Hall, Aristea S Galanopoulou
• Journal: Epilepsia (Epilepsia) Vol. 55 Issue 1 Pg. 94-102 (Jan 2014) ISSN: 1528-1167 [Electronic] United States
• PMID: 24321005 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Chemical References

• (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid
• Anticonvulsants
• Proline

Topics

• Animals
• Animals, Newborn
• Anticonvulsants (therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Infant
• Male
• Maze Learning (drug effects)
• Monitoring, Physiologic
• Proline (analogs & derivatives, therapeutic use)
• Rats
• Spasms, Infantile (drug therapy)