Yan Meng-Qi, Qiu Xiao-Yun, Zhang Shuo, Yu Xue-Min, Sun Min-Juan, Yang Yuan-Zhi, Gong Yi-Wei, Zou Shuang, Li Meng-Han, Fei Fan, Du Yu, Wang Yi, Tang Ying-Ying, Chen Zhong, Xu Ceng-Lin
Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Science, The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
Acta Pharmacol Sin. 2025 Jun 17. doi: 10.1038/s41401-025-01594-8.
Pharmacoresistance remains intractable in epilepsy, necessitating in-depth mechanism investigations. Cumulative data have pointed to active neuroinflammation in pharmacoresistant epilepsy, but the process between neuroinflammation and pharmacoresistance remains unknown. In this study we investigated how severe neuroinflammation altered anti-seizure drugs (ASMs) pharmacology. Hippocampal kindling or kainic acid-induced temporal lobe epilepsy (TLE) models were established in mice that had received intra-hippocampal LPS injection. Acute hippocampal slices were prepared; current-clamp recording was made in hippocampal pyramidal neurons to assess the impact of ASMs on neuronal excitability and sodium channels. We showed that intra-hippocampal LPS injection resulted in higher inflammatory cytokine levels in the hippocampus. LPS induced-neuroinflammation significantly decreased the antiseizure efficacy of phenytoin (PHT), carbamazepine (CBZ) and rufinamide (RUF), all the ASMs tested were unable to alleviate the seizure severities. We observed the "off-target" phenomena of ASMs, i.e. ASMs' loss of ability to suppress the firing of action potentials and the amplitudes of sodium currents in hippocampal pyramidal neurons from LPS-treated mice. We demonstrated that LPS induced-neuroinflammation promoted the degradation of spermine, an essential polyamine linked with ASM performance on sodium channels, through upregulating the catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT). Intra-hippocampal injection of SSAT agonist DENSPM mimicked LPS-induced "off-target" phenomena of ASMs, whereas injection of SSAT antagonist diminazene aceturate into hippocampus reversed the "off-target" phenomenon of ASMs in LPS-treated mice. Finally, intrahippocampal injection of spermine restored the efficacy of ASMs on action potential firings and sodium currents, resulting in the reversal of pharmacoresistance in LPS-treated TLE models. These results provide new evidence that neuroinflammation causes pharmacoresistance in TLE via promoting spermine degradation, and highlight spermine supplementation as a promising therapy for pharmacoresistant TLE.
癫痫中的药物抵抗问题仍然难以解决，这就需要深入研究其机制。越来越多的数据表明，药物抵抗性癫痫中存在活跃的神经炎症，但神经炎症与药物抵抗之间的过程仍不清楚。在本研究中，我们调查了严重神经炎症如何改变抗癫痫药物（ASMs）的药理学特性。在接受海马内注射脂多糖（LPS）的小鼠中建立海马点燃或 kainic 酸诱导的颞叶癫痫（TLE）模型。制备急性海马切片；在海马锥体神经元中进行电流钳记录，以评估 ASMs 对神经元兴奋性和钠通道的影响。我们发现，海马内注射 LPS 导致海马中炎症细胞因子水平升高。LPS 诱导的神经炎症显著降低了苯妥英（PHT）、卡马西平（CBZ）和卢非酰胺（RUF）的抗癫痫疗效，所有测试的 ASMs 均无法减轻癫痫严重程度。我们观察到 ASMs 的“脱靶”现象，即 ASMs 失去了抑制 LPS 处理小鼠海马锥体神经元动作电位发放和钠电流幅度的能力。我们证明，LPS 诱导的神经炎症通过上调分解代谢酶亚精胺/精胺 N(1)-乙酰转移酶（SSAT）促进了精胺的降解，精胺是一种与 ASMs 对钠通道性能相关的必需多胺。海马内注射 SSAT 激动剂 DENSPM 模拟了 LPS 诱导的 ASMs“脱靶”现象，而向海马内注射 SSAT 拮抗剂乙酰氨基苯脒则逆转了 LPS 处理小鼠中 ASMs 的“脱靶”现象。最后，海马内注射精胺恢复了 ASMs 对动作电位发放和钠电流的疗效，导致 LPS 处理的 TLE 模型中药物抵抗的逆转。这些结果提供了新的证据，表明神经炎症通过促进精胺降解导致 TLE 中的药物抵抗，并强调补充精胺作为药物抵抗性 TLE 的一种有前景的治疗方法。
