Novel agents and targets for treating a rat model of infantile spasms
Briggs, Stephen Warwick
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Infantile spasms are age-specific epileptic seizures that manifest in infantile epileptic encephalopathies, and have poor outcomes. First, I discuss the safety and efficacy of a novel therapeutic candidate, the vigabatrin analogue CPP-115, for treating spasms in the multiple-hit rat model of infantile spasms. I then investigate the role of the inflammatory cytokine interleukin-1beta in inducing and maintaining spasms and associated behavioral deficits.;Methods: For the CPP-115 study, neonatal male rats were induced to have spasms using the multiple-hit rat model, then were injected once daily intraperitoneally with one of several doses of CPP-115. Rats were followed for spasms and neurodevelopmental behaviors. A separate group underwent video-EEG monitoring to demonstrate the response of electroclinical spasms to a single injection of CPP-115. The study was conducted with blinding to treatment allocation.;For the interleukin-1beta study, neonatal rats were injected with one of several doses of interleukin- 1beta and followed for spasms and developmental milestones. A subset was followed by video-EEG for electroclinical spasms. Another subset was treated with an interleukin-1 receptor antagonist and followed for spasms. Brains were processed for histology.;Results: CPP-115 reduces spasms in a dose-dependent manner for 2-3 days, but does not improve behavioral outcomes. I identified CPP-115 treatment protocols with better efficacy on spasms and tolerability than vigabatrin. Intracortical interleukin-10 caused behavioral spasms in a dose-dependent manner for up to five days, and electroclinical spasms on video-EEG, but minimal behavioral deficits. Treatment with interleukin-1 receptor antagonist reduced spasms; the timing of its effect was dependent on the administration route.;Conclusions: CPP-115 is a safe and effective drug for reducing spasms in the multiple-hit model of spasms. It has a longer duration of efficacy than vigabatrin. CPP-115 is in phase I clinical testing with orphan drug status for the treatment of infantile spasms.;Intracortical interleukin-1beta can cause spasms in neonatal rats, but the severity of the spasms, associated pathology, and comorbidities is less than in the multiple-hit model. Antagonism of the interleukin-1beta pathway reduces spasms only when given close in time to the interleukin-1beta injection.
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