Abstracts

Rationale: Infantile spasms (IS) are age-specific epileptic seizures of infantile epileptic syndromes such as West syndrome. IS typically manifest as clusters of ?exion or extension spasms and have poor neurodevelopmental outcomes and dire prognosis. Better therapies are required. The classical ketogenic diet is one of the available adjunctive treatments for various epilepsies, including IS. Decanoic acid (DEC) is one of the fats provided in the medium chain triglyceride (MCT) ketogenic diet. MCTs have been suggested to have some therapeutic potential, but their efficacy has not been directly tested in IS. Here, we use the multiple-hit rat model of IS due to structural lesion to investigate DEC, administered after the onset of spasms, for its efficacy in reducing spasms. Methods: On postnatal day (PN) 3, Sprague-Dawley male rats received right intracerebral injections of doxorubicin (DOX) and lipopolysaccharide (LPS) under isoflurane anesthesia, followed by intraperitoneal (i.p.) injection of systemic p-chlorophenylalanine (PCPA) on PN5. Daily monitoring of weights, surface righting time (SRT), open field activity (OFA), and negative geotaxis (NG) were scored from PN3-PN5. Animals were video-monitored on PN4 for 1 hour prior and 5 hours after drug or vehicle administration and on PN5 for two 2-hour sessions. Using a randomized, blinded, vehicle-controlled, dose-response study design, DEC (0.1, 0.25, 0.5, or 5mM) or vehicle was given i.p. on PN4 PM, as a single injection in each group (VEH: n=14, 0.1mM DEC: n =13, 0.25 mM DEC: n=10, 0.5mM DEC: n=9, 5mM DEC: n=7). On PN5, pups were euthanized with pentobarbital and brains were frozen for histology. Statistics on log-transformed data of raw or normalized over the baseline frequencies of spasms used a linear mixed model accounting for repeated measures. Results: The highest dose of DEC [5mM DEC] reduced both raw and normalized spasms rates in the DLP rats that received it compared to those that received the VEH at the 2^nd and 4^th hour after the drug administration on PN4 (P<0.05). There were no differences in mortality, weights, weight gain rates and the battery of neurodevelopmental tests till PN5 and the drug was well tolerated. Conclusions: The highest dose of DEC suppressed spasms during the 2^nd and 4^th post-drug injection hour with no adverse effects seen in the pups and without requiring additional ketogenic dietary restrictions. This suggests MCTs as propitious pharmacologic candidates for further exploration of their potential in the treatment of IS. Funding: Funded by NINDS NS091170 and U54 NS100064.