Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions

• Published in: Epilepsia (Copenhagen) Vol. 62; no. 8; pp. 1985 - 1999
• Main Authors: Akman, Ozlem, Briggs, Stephen W., Mowrey, Wenzhu B., Moshé, Solomon L., Galanopoulou, Aristea S.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2021
• Subjects: Animals; Basal ganglia; Convulsions & seizures; Disease Models, Animal; Doxorubicin; EEG; Electroencephalography; Epilepsy; Etiology; Infants; Lennox Gastaut Syndrome; Lesions; Lipopolysaccharides; Male; Mice; mTOR; Rapamycin; Rats; Rodents; Seizures; Sirolimus; Sleep; Sleep and wakefulness; Spasm; West syndrome; epilepsy; sleep; mTOR; West syndrome; Lennox-Gastaut syndrome
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.16975

Objective Infantile spasms may evolve into persistent epilepsies including Lennox‐Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple‐hit model) or focal cortical inflammation and determined the anti‐epileptogenic effects of pulse‐rapamycin, previously shown to stop spasms in multiple‐hit rats. Methods Spasms were induced in 3‐day‐old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple‐hit model) infusions. Controls and sham rats were used. Separate multiple‐hit rats received pulse‐rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video‐EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment. Results Motor‐type seizures developed in 66.7% of multiple‐hit rats, usually from sleep, but were reduced in the pulse‐rapamycin–treated group (20%, p = .043 vs multiple‐hit) and rare in other groups (0–9.1%, p < .05 vs multiple‐hit). Spike‐and‐wave bursts had a slower frequency in multiple‐hit rats (5.4–5.8Hz) than in the other groups (7.6–8.3Hz) (p < .05); pulse rapamycin had no effect on the hourly spike‐and‐wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow‐wave‐sleep (17.2%), which was increased in multiple‐hit rats (71.6%, p = .003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p = .043). Multiple‐hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups. Significance Structural corticohippocampal/basal ganglia lesions increase the risk for post‐infantile spasms epilepsy, Lennox‐Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti‐epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep.