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

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.