Honokiol-induced SIRT3 upregulation protects hippocampal neurons by suppressing inflammatory processes in pilocarpine-induced status epilepticus.

Status epilepticus (SE), a continuous and self-sustaining epileptic seizure lasting more than 30 min, is a neurological emergency that can cause severe brain injuries and increase the risk for the development of epilepsy. Over the past few decades, accumulating evidence has suggested the importance of brain inflammation in the pathogenesis of epilepsy. Honokiol (HNK), a pharmacological activator of sirtuin 3 (SIRT3), is a bioactive compound extracted from the bark or leaves of Magnolia plants that possesses therapeutic benefits for preventing the development of inflammatory injury. However, the therapeutic effects of HNK against epileptic brain injury via regulating molecular mechanisms related to neuroinflammation remains elusive. Therefore, the present study investigated the effects of HNK on pilocarpine-induced status epilepticus (PCSE) and the therapeutic benefits of HNK in regulating inflammatory processes in the hippocampus. Treatment with HNK before PCSE induction attenuated the initiation of behavioral seizures. Post-treatment with HNK after SE onset increased SIRT3 expression, which mitigated glial activation, including reactive astrocytes and activated microglia, in the hippocampus following PCSE. Moreover, HNK treatment reduced the activation of the nuclear factor-κB/nucleotide-binding domain leucine-rich repeat with a pyrin-domain containing 3 inflammasome pathway, thereby inhibiting the production of interleukin-1β pro-inflammatory cytokine, subsequently alleviating PCSE-triggered apoptotic neuronal death in the hippocampus. These results indicate that HNK-induced SIRT3 upregulation has the potential to prevent the progression of epileptic neuropathology through its anti-inflammatory properties. Therefore, the present study suggests that HNK is a natural therapeutic agent for epileptic brain injury.