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

Acta Pharmacologica Sinica (2025)Cite this article

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.

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Fig. 1: Intra-hippocampal LPS treatments caused pharmacoresistance in hippocampal kindled mice.
Fig. 2: The impact of LPS treatments on the inhibitory efficacy of PHT, CBZ and RUF on hippocampal pyramidal neurons.
Fig. 3: LPS treatments led to the “off-target” phenomenon of the ASMs on maximum activated sodium currents in hippocampal pyramidal neurons.
Fig. 4: Promoted spermine degradation by SSAT underlies the “off-target” phenomenon of ASMs and pharmacoresistance.
Fig. 5: Promoted spermine degradation by increased SSAT was responsible for the “off-target” phenomenon of ASMs caused by LPS-induced neuroinflammation.
Fig. 6: Spermine supplementation reversed the “off-target” phenomenon of ASMs and restored their inhibitory efficacy on neuronal excitabilities.
Fig. 7: Exogenous spermine overcomes pharmacoresistance caused by LPS-induced neuroinflammation in kindled mice.
Fig. 8: Spermine supplementation powerfully increased the anti-seizure efficacy of ASMs on LPS-treated mice in the acute KA tests.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82173796, 82374064, 82330116), the Natural Science Foundation of Zhejiang Province (No. LQ24H310002), and the Research Project of Zhejiang Chinese Medical University (2023JKZDZC04).

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  1. These authors contributed equally: Meng-qi Yan, Xiao-yun Qiu, Shuo Zhang, Xue-min Yu

Authors and Affiliations

  1. 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

    Meng-qi Yan, Xiao-yun Qiu, Shuo Zhang, Xue-min Yu, Min-juan Sun, Yuan-zhi Yang, Yi-wei Gong, Shuang Zou, Meng-han Li, Fan Fei, Yu Du, Yi Wang, Zhong Chen & Ceng-lin Xu

  2. Department of Pharmacy, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Ying-ying Tang

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Contributions

CLX, ZC and MQY designed research. MQY, XYQ, SZ and XMY performed research. MQY, XYQ, SZ, XMY, MJS, YZY, YWG, SZ, MHL and FF analyzed data. MQY, ZC and CLX wrote the paper. YD, YW, and YYT revised the paper. YYT, CZ and CXL supervised this study.

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Correspondence to Zhong Chen or Ceng-lin Xu.

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Yan, Mq., Qiu, Xy., Zhang, S. et al. Neuroinflammation leads to pharmacoresistance in temporal lobe epilepsy via promoting spermine degradation. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01594-8

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