Dataset Information

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

ABSTRACT: Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a ?-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.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.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.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.

SUBMITTER: Briggs SW

PROVIDER: S-EPMC4102583 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Briggs Stephen W SW Mowrey Wenzhu W Hall Charles B CB Galanopoulou Aristea S AS

Epilepsia 20131028 1

<h4>Objective</h4>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 whi ...[more]

PMID: 24321005

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Project description:Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over ?-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms.

Dataset Information

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

Publications

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

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