浙江中医药大学徐层林小组近日取得一项新成果。经过不懈努力，他们报道了神经炎症通过促进精胺降解导致颞叶癫痫的耐药。这一研究成果发表在2025年6月17日出版的国际学术期刊《中国药理学报》上。

在这项研究中，研究人员研究了严重的神经炎症如何改变抗癫痫药物（ASMs）的药理学。建立海马内LPS注射小鼠海马点燃或凯因酸诱发的颞叶癫痫（TLE）模型。制备急性海马切片；对海马锥体神经元进行电流钳记录，评估肌电刺激对神经元兴奋性和钠通道的影响。课题组人员发现海马内注射LPS导致海马内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）和鲁非胺（RUF）的抗癫痫作用，所有抗癫痫药均不能减轻癫痫发作的严重程度。该团队观察到ASMs的“脱靶”现象，在LPS处理的小鼠海马锥体神经元中，ASMs抑制动作电位放电和钠电流振幅的能力丧失。该课题组人员证明，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。精胺是一种与钠通道上ASM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的“脱靶”现象，而海马内注射SSAT拮抗剂醋酸苯缩胺逆转了LPS处理小鼠ASMs的“脱靶”现象。最后，海马内注射精胺恢复了ASMs对动作电位放电和钠电流的作用，从而逆转了LPS处理的TLE模型的耐药。这些结果为神经炎症通过促进精胺降解来促进TLE耐药提供了新的证据，并突出了补充精胺作为耐药TLE的一种有前景的治疗方法。

研究人员表示，癫痫的耐药问题仍然难以解决，需要深入的机制研究。积累的数据表明，抗药癫痫中存在活动性神经炎症，但神经炎症与抗药之间的过程尚不清楚。

附：英文原文

Title: Neuroinflammation leads to pharmacoresistance in temporal lobe epilepsy via promoting spermine degradation

Author: 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

Issue&Volume: 2025-06-17

Abstract: 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.

DOI: 10.1038/s41401-025-01594-8

Source: https://www.nature.com/articles/s41401-025-01594-8