Oxysterols are products of cholesterol oxidation and play important roles in a number of processes, including signaling, development, metabolism, membrane homeostasis, inflammation and immune function. It has been demonstrated that 24S-hydroxycholesterol (24-OHC) can modulate neuronal functions, with potential relevance to the hyperexcitability underlying seizures. 24-OHC is produced in a brain by the CYP46A1 enzyme from cholesterol. The goal of our study was to investigate the relationship between the serum levels of 24-OHC in mice and the development of seizures in a kindling animal model induced by pentylenetetrazol (PTZ).

Outbred mice were injected with subthreshold dosages of PTZ (35 mg/kg) every other day for 30 days. Seizure activity was assessed using the Racine scale. To achieve a reduction in cholesterol 24-OHC levels in the brain, we used the inhibitor of CYP46A1, voriconazole (60 mg/kg, n=10), and for increasing 24-OHC levels, we used a low dose of efavirenz (0,09 mg/kg, n=10). We also included a control group control group (n=10). Voriconazole was injected peritonial for 5 days before PTZ treatment, and efavirenz was delivered perorally for 2 weeks before PTZ treatment. Both substances had a maintenance course during PTZ treatment.

During voriconazole treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased compared to those in vehicle-treated mice. The augmentation of 24-OHC levels induced high-grade and -intensity seizures. The duration and onset of seizure did not change compared to that in the control group.

Thus, the experimental data show that changing 24S-hydroxycholesterol levels in the blood of mice may contribute to the development of PTZ-induced seizures.