A high seizure burden increases brain concentrations of specialized pro-resolving mediators in the Scn1a+/- mouse model of Dravet syndrome

Ka Lai Yip; Cilla Zhou; Lyndsey L Anderson; Nicole A Hawkins; Jennifer A Kearney; Jonathon C Arnold

doi:10.1016/j.prostaglandins.2024.106943

A high seizure burden increases brain concentrations of specialized pro-resolving mediators in the Scn1a^+/- mouse model of Dravet syndrome

Prostaglandins Other Lipid Mediat. 2024 Dec 17:176:106943. doi: 10.1016/j.prostaglandins.2024.106943. Online ahead of print.

Authors

Ka Lai Yip¹, Cilla Zhou¹, Lyndsey L Anderson¹, Nicole A Hawkins², Jennifer A Kearney², Jonathon C Arnold³

Affiliations

¹ Discipline of Pharmacology, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2050, Australia; Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, NSW 2050, Australia; Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
² Department of Pharmacology, Feinberg School of Medicine, Northwestern University, IL 60611, USA.
³ Discipline of Pharmacology, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2050, Australia; Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, NSW 2050, Australia; Brain and Mind Centre, The University of Sydney, NSW 2050, Australia. Electronic address: jonathon.arnold@sydney.edu.au.

PMID: 39701411
DOI: 10.1016/j.prostaglandins.2024.106943

Abstract

Objective: Dravet syndrome is a severe, intractable epilepsy in which 80 % of patients have a de novo mutation in the gene SCN1A. We recently reported that a high seizure burden increased hippocampal concentrations of an array of pro-inflammatory prostaglandins in the Scn1a^+/- mouse model of Dravet syndrome. This raised the possibility that a high seizure burden might also trigger the accumulation of specialized pro-resolving mediators that facilitate the resolution of neuroinflammation and brain repair. The present study therefore aimed to examine whether a high seizure burden increased hippocampal concentrations of various specialized pro-resolving mediators in the Scn1a^+/- mouse model of Dravet syndrome.

Methods: Scn1a^+/- mice at postnatal day 21 (P21) were primed with a single hyperthermia-induced seizure event to induce a high seizure burden. On P24 primed Scn1a^+/- mice with a high seizure burden, unprimed naïve Scn1a^+/- mice and wild-type (WT) mice were euthanized and hippocampal tissue was collected for analysis of various specialized pro-resolving mediators using liquid chromatography mass spectrometry.

Results: Scn1a^+/- mice with a high seizure burden showed increased hippocampal concentrations of the pro-inflammatory leukotrienes B4 and E4. Further, a high seizure burden increased hippocampal concentrations of various special pro-resolving mediators, including the maresins (maresin1), D-series resolvins (RVD1 and RVD4), and protectin (PCTR1). To further characterize these changes, we determined the mRNA expression of lipoxygenase genes, as these synthetic enzymes are common across classes of specialized pro-resolving mediators. However, hippocampal expression of Alox5, Alox12 and Alox15 were not influenced by a high seizure burden.

Significance: We report for the first time that a high seizure burden increases the hippocampal concentrations of various specialized pro-resolving mediators in Scn1a^+/- mice. This provides a platform for future studies to examine whether modulation of these mediators might be exploited to reduce seizures and facilitate brain repair in intractable epilepsy syndromes.

Keywords: Dravet syndrome; Inflammation resolution; Seizure; Specialized pro-resolving mediator.