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<p> Background: Neuroinflammation and mitophagy play crucial roles in temporal lobe epilepsy (TLE) pathogenesis, which follows the initial precipitating insult such as status epilepticus (SE). We aimed to explore the relationship between the NLRC4 inflammasome and mitophagy and their roles in TLE pathogenesis. Methods: We developed an SE mouse model, representing the acute phase of TLE, by injecting kainic acid (KA) into the unilateral hippocampus of mice. Seizure activity was recorded; afterward, the expression of NLRC4 and its downstream proteins was assessed. Subsequently, neuronal damage and mitochondrial ultrastructure and function were assessed. Results: NLRC4 was activated and highly expressed in the hippocampus of SE mice. NLRC4 upregulation in the hippocampus shortened seizure latency, aggravated seizure severity, and increased hippocampal neuronal loss in SE mice. Mitophagy inhibition prolonged seizure latency, attenuated seizure severity, and reduced hippocampal neuron loss in SE mice. Furthermore, mitophagy inhibition decreased the expression of NLRC4 and its downstream proteins in the hippocampus 24&#xa0;h after SE. In addition, mitophagy inhibition alleviated mitochondrial crista fracture and autophagosome formation in the hippocampus 24&#xa0;h after SE. In KA-treated HT22 cells, mitophagy inhibition alleviated the decrease in mitochondrial membrane potential and the increase in Reactive Oxygen Species (ROS) release. Conclusions: Mitophagy inhibition suppresses seizures by inhibiting NLRC4 expression in the hippocampus of KA-induced SE mice. Targeting the crosstalk of mitophagy and NLRC4 inflammasome may offer a novel potential therapeutic strategy for neuroinflammation-related epileptogenesis of TLE after SE.</p>

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Mitophagy Inhibition Suppresses Seizures in Status Epilepticus Mice by Decreasing Hippocampal NLRC4 Expression

  • 期刊论文

  • 发表日期：

    2026年2月5日

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  • Zhi-Cheng Dong,
  • Min Liu,
  • Jin-Yi Zhou,
  • Li-Qun Geng,
  • Mei Li,
  • Xu-Qin Chen

摘要

Background: Neuroinflammation and mitophagy play crucial roles in temporal lobe epilepsy (TLE) pathogenesis, which follows the initial precipitating insult such as status epilepticus (SE). We aimed to explore the relationship between the NLRC4 inflammasome and mitophagy and their roles in TLE pathogenesis. Methods: We developed an SE mouse model, representing the acute phase of TLE, by injecting kainic acid (KA) into the unilateral hippocampus of mice. Seizure activity was recorded; afterward, the expression of NLRC4 and its downstream proteins was assessed. Subsequently, neuronal damage and mitochondrial ultrastructure and function were assessed. Results: NLRC4 was activated and highly expressed in the hippocampus of SE mice. NLRC4 upregulation in the hippocampus shortened seizure latency, aggravated seizure severity, and increased hippocampal neuronal loss in SE mice. Mitophagy inhibition prolonged seizure latency, attenuated seizure severity, and reduced hippocampal neuron loss in SE mice. Furthermore, mitophagy inhibition decreased the expression of NLRC4 and its downstream proteins in the hippocampus 24 h after SE. In addition, mitophagy inhibition alleviated mitochondrial crista fracture and autophagosome formation in the hippocampus 24 h after SE. In KA-treated HT22 cells, mitophagy inhibition alleviated the decrease in mitochondrial membrane potential and the increase in Reactive Oxygen Species (ROS) release. Conclusions: Mitophagy inhibition suppresses seizures by inhibiting NLRC4 expression in the hippocampus of KA-induced SE mice. Targeting the crosstalk of mitophagy and NLRC4 inflammasome may offer a novel potential therapeutic strategy for neuroinflammation-related epileptogenesis of TLE after SE.