Tacrolimus protects hippocampal neurons of rats with status epilepticus through suppressing oxidative stress and inhibiting mitochondrial pathway of apoptosis

Abstract

Objective: To investigate the mechanisms underlying the neuroprotective effect of tacrolimus (FK506) on the hippocampal neurons of rats with status epilepticus (SE).

Method: A total of 126 male Wistar rats were randomly and equally divided into the control group, the epilepsy group, and the epilepsy + FK506 group. The epilepsy group and the epilepsy + FK506 group were both injected with pilocarpine to establish SE models. The epilepsy + FK506 group was pretreated with FK506 at 24 h and 1 h prior to pilocarpine injection. The contents of nitric oxide (NO), nitric oxide synthase (NOS), malondialdehyde (MDA), and apoptosis-inducing factor (AIF) of the hippocampus were measured. The expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in the hippocampus was determined by immunohistochemistry. Mitochondrial membrane potential (MMP) and mitochondria size were also detected by flow cytometry.

Results: FK506 could increase the survival of neurons in the hippocampus. Compared with the epilepsy group, the levels of NO, NOS (including nNOS and iNOS), and MDA were obviously decreased by FK506 (P < 0.05). Moreover, FK506 reversed the SE-induced MMP reduction and mitochondrial expansion (P < 0.05). Besides, compared with the epilepsy group, FK506 significantly increased the AIF level in the mitochondrial, but decreased that in the nuclear fractions, respectively (P < 0.05).

Conclusion: FK506 plays an important role in neuroprotection, possibly through suppressing oxidative stress and inhibiting the mitochondrial pathway of apoptosis.

Keywords: Mitochondrial pathway of apoptosis; Nitric oxide; Oxidative stress; Status epilepticus; Tacrolimus.