Repurposing of cholesterol-lowering agents in status epilepticus: A neuroprotective effect of simvastatin

Abstract

The increase of cholesterol synthesis after a status epilepticus may lead to excitotoxic processes, neuronal loss and favor the appearance of spontaneous epileptic seizures. Lowering cholesterol content could be a neuroprotective strategy. Here, we evaluated the protective effect of simvastatin administrated daily for 14 days, after the induction of a status epilepticus by intrahippocampal injection of kainic acid in mice. The results were compared to those obtained from mice showing a kainic acid-induced status epilepticus, treated daily with a saline solution, and from mice injected with a control phosphate-buffered solution without any status epilepticus. We first assessed the antiseizure effects of simvastatin by performing video-electroencephalographic recordings during the first three hours after kainic acid injection and continuously between the fifteenth and the thirty-first days. Mice treated with simvastatin had significantly fewer generalized seizures during the first three hours without a significant effect on generalized seizures after two weeks. There was a trend for fewer hippocampal electrographic seizures after two weeks. Secondly, we evaluated the neuroprotective and anti-inflammatory effects of simvastatin by measuring the fluorescence of neuronal and astrocyte markers on the thirtieth day after status onset. We found that simvastatin reduced CA1 reactive astrocytosis, demonstrated by a significant 37% decrease in GFAP-positive cells, and that simvastatin prevented the neuronal loss in CA1, demonstrated by a significant 42% increase in the NeuN-positive cells, as compared to the findings in mice with kainic acid-induced status epilepticus treated by a saline solution. Our study confirms the interest of cholesterol-lowering agents, and in particular simvastatin, in status epilepticus and paves the way for a clinical pilot study to prevent neurological sequelae after status epilepticus. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Keywords: EEG; Kainic acid; Neuroprotection; Simvastatin; Status epilepticus.