piperidines and Seizures--Febrile

Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a. In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a. Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a. This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Topics: Animals; Cholesterol 24-Hydroxylase; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Mice; Mortality, Premature; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Piperidines; Pyridines; Seizures; Seizures, Febrile; Sudden Unexpected Death in Epilepsy

It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

Topics: Aging; Animals; Benzoxazines; Cannabinoid Receptor Antagonists; Cyclohexanones; Gene Expression Regulation; Hippocampus; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Lipoprotein Lipase; Mice; Mice, Knockout; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Small Interfering; Seizures; Seizures, Febrile; Signal Transduction; Tissue Culture Techniques

Febrile seizures (FSs), the most common type of convulsive events in infants, are closely associated with temporal lobe epilepsy (TLE) in adulthood. It is urgent to investigate how FSs promote epileptogenesis and find the potential therapeutic targets. In the present study, we showed that the phosphorylation of GluN2B Tyr1472 gradually reached peak level at 24h after prolonged FSs and remained elevated during 7days thereafter. IL-1β treatment alone, which in previous study mimicked the effect of prolonged FSs on adult seizure susceptibility, increased GluN2B Tyr1472 phosphorylation. Both IL-1 receptor antagonist (IL-1Ra) and IL-1R1 deletion were sufficient to reverse the prolonged FSs induced hyper-phosphorylation of GluN2B Tyr1472. GluN2B antagonist ifenprodil showed a wide therapeutic time-window (3days) to reverse the enhanced seizure susceptibility after prolonged FSs or IL-1β treatment. Our study demonstrated that GluN2B phosphorylation at Tyr1472 site mediated by the transient increase of IL-1β was involved in the enhanced adult seizure susceptibility after prolonged FSs, implicating GluN2B-containing NMDAR is a new potential drug target with a wide therapeutic time window to prevent epileptogenesis in patients with infantile FSs.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Disease Susceptibility; Electroshock; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Exploratory Behavior; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Kainic Acid; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1 Type I; Receptors, N-Methyl-D-Aspartate; Seizures, Febrile

Topics: Adult; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Child, Preschool; Clinical Trials as Topic; Epilepsy; Humans; Models, Neurological; Piperidines; Pyrazoles; Rimonabant; Seizures, Febrile