Related Experiment Video
Updated: May 5, 2026
Pentylenetetrazole-Induced Kindling Mouse Model
Published on: June 12, 2018
CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms
Stephen W Briggs1, Wenzhu Mowrey, Charles B Hall
1Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, U.S.A; Laboratory of Developmental Epilepsy and Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, U.S.A.
Insights
CPP-115, a vigabatrin analogue, effectively reduced infantile spasms (IS) in a rat model at lower doses than vigabatrin. This new treatment shows promise for IS with improved tolerability compared to existing options.
Area of Science:
- Neuroscience
- Pharmacology
- Pediatric Neurology
Background:
- Infantile spasms (IS) are a severe epilepsy syndrome with limited treatment options and poor outcomes.
- Vigabatrin, a first-line treatment, carries risks of retinal toxicity.
- CPP-115 is a novel vigabatrin analogue designed to reduce retinal toxicity while maintaining efficacy.
Purpose of the Study:
- To evaluate the efficacy and tolerability of CPP-115 in the multiple-hit rat model of infantile spasms.
- To compare CPP-115's effects with those of vigabatrin in a preclinical setting.
Main Methods:
- A randomized, blinded, vehicle-controlled, dose-response study was conducted in male rats using the multiple-hit IS model.
- CPP-115 was administered daily or as a single injection, with intermittent video-EEG monitoring.
- Neurodevelopmental and cognitive functions were assessed through various behavioral tests.
Main Results:
- Lower doses of CPP-115 (0.1-1 mg/kg/day) effectively reduced spasms without increasing mortality.
- A higher dose (5 mg/kg/day) led to earlier spasm reduction but was lethal.
- Single injections of CPP-115 showed acute but transient spasm reduction; neurodevelopmental outcomes were unaffected.
Conclusions:
- CPP-115 demonstrates proof-of-concept efficacy in reducing infantile spasms in a preclinical model.
- CPP-115 was effective at lower, better-tolerated doses compared to vigabatrin.
- Further optimization of CPP-115 treatment protocols is warranted, suggesting its potential as a safer alternative for IS treatment.
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.
Related Concept Videos
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...
01:29Spasmolytic Agents: Chemical Classification
A major class of centrally acting spasmolytics is the α2-agonist, such as tizanidine. These drugs bind to α2-adrenoceptors, inhibiting the release of the excitatory neurotransmitter glutamate. They also...
01:14Antiepileptic Drugs: Glutamate Antagonists
01:28Classification of Skeletal Muscle Relaxants
Peripherally acting skeletal muscle relaxants interfere with the neurotransmission at the neuromuscular end plate to induce paralysis during...
01:17Antiepileptic Drugs: Calcium Channel Blockers
Calcium channel blockers exert their antiepileptic effects by targeting T-type calcium channels, which are integral to transmitting nerve signals in the central nervous system. These channels allow the passage of calcium ions, which are vital for neuronal communication. By inhibiting T-type calcium channels, calcium channel blockers effectively reduce the release of neurotransmitters and...