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Publications

Journal Article Ppublish

PubMed: 42453418 DOI: 10.1016/j.apsb.2026.04.011

Acquired pharmacoresistance in temporal lobe epilepsy is driven by Na v1.6-mediated subicular hyperexcitability.

Acta Pharm Sin B 16(7):4442-4458

Authors: Yuanzhi Yang, Menghan Li, Minjuan Sun, Shuo Zhang, Xiongfeng Guo, Shuangshuang Wu, Yiwei Gong, Lan Huang, Tong Liu, Junxiu Ye, Xiangyu Ma, Xiaoyun Qiu, Shuang Wang, Fan Fei, Yu Du, Yi Wang, Zhong Chen, Cenglin Xu

Affiliations

  • Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China. Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China.
  • Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310050, China.

Abstract

Pharmacoresistance to anti-seizure medications (ASMs) remains a major unmet challenge in temporal lobe epilepsy (TLE), and occurs diversely, as classified to primary or acquired manner. The pathophysiological underpinnings of acquired pharmacoresistance remain elusive. Here, using a hippocampal kindling mouse model, we established that prolonged lamotrigine (LTG) treatment-either during or after kindling-induces broad-spectrum resistance to multiple ASMs, effectively recapitulating clinical patterns of acquired pharmacoresistance. Multimodal interrogation revealed hyperexcitability of subicular pyramidal neurons as a critical factor in pharmacoresistance, characterized by elevated c-Fos expression specifically within the subiculum, as well as hyperexcitability of subicular glutamatergic pyramidal neurons. This hyperexcitability phenotype stemmed from Na v1.6 upregulation, driving both enhanced persistent sodium current (I NaP) and a pro-excitatory shift in voltage-dependent activation kinetics of voltage-gated sodium channel (VGSC). Crucially, pharmacological activation of subicular Na v1.6 sufficed to induce acquired pharmacoresistance in pharmaco-responsive mice. Conversely, subiculum-specific Na v1.6 knockdown in pyramidal neurons (but not GABAergic neurons) prevented or reversed pharmacoresistance, while analogous genetic manipulation in the CA1 had no such impact. Chemogenetic inhibition of subicular pyramidal neurons (mimicking ASM effects) restored drug responsiveness, directly implicating compensatory increases in Na v1.6 offsetting ASM's inhibitory function on subicular excitability in acquired pharmacoresistance. These findings collectively identify Na v1.6 upregulation in subicular pyramidal neurons as a critical driver of acquired pharmacoresistance in TLE, highlighting a novel therapeutic target for refractory epilepsy.

MeSH

Up-Regulation, Epilepsy, Neurons, Epilepsy, Temporal Lobe, Therapeutics, Pyramidal Cells, Temporal Lobe