Haifeng Zhang1  · Tiantian Su1  · Xiaoke Wu2  · Mengmeng Shi3

1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 

2 Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun 130021, China 

3 Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Abstract

There is a vicious cycle between brain metabolism and epileptic seizures that compounds the deleterious consequences of seizures. Human epilepsy samples implicate cholesterol 25-hydroxylase (CH25H) in linking lipid metabolism and immunity. CH25H expression increased in microglia after status epilepticus, with its product 25-hydroxycholesterol (25-HC) accumulating in the hippocampus and blood. Thus, we generated microglia-specific CH25H knockdown mice to study the role of CH25H specifically in epilepsy. CH25H knockdown inhibited the assembly and activation of NLRP3 inflammasome and restrained the loss of neurons in the hippocampal area in epileptic mice. More importantly, CH25H knockdown reduced the number of recurrent seizures and time in seizure by electroencephalogram recording, which was partly reversed after 25-HC treatment. Untargeted metabolomics showed that another lipid metabolite, arachidonic acid, might be a potential biomarker of CH25H-mediated epilepsy. These findings suggest that microglial CH25H regulated the status epilepticus in a hydroxylase-dependent mechanism.

Keywords

Epilepsy; Microglia; CH25H; 25-HC; Neuronal loss; NLRP3

[SpringerLink]