Lithium ameliorates spinal cord injury through endoplasmic reticulum stress-regulated autophagy and alleviated apoptosis through IRE1 and PERK/eIF2α signaling pathways

IF 3.1 4区医学 Q2 CLINICAL NEUROLOGY Journal of Neurorestoratology Pub Date : 2023-10-12 DOI:10.1016/j.jnrt.2023.100081

Fang Wang , Chengyi Zhang , Qiongchi Zhang , Jiaxi Li , Yuewen Xue , Xijing He , Fengtao Li

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Abstract

Objective

This study aims to investigate the role of apoptosis and autophagy under endoplasmic reticulum (ER) stress in a lithium-treated SCI model.

Methods

We established a rat thoracic 10 (T10) spinal cord contusion model and observed its therapeutic effect by intraperitoneal (IP) injection of lithium. Histological and behavioral recovery with or without lithium injection were evaluated after rat spinal cord injury. In addition, we employed an oxygen-glucose deprivation (OGD)-PC12 cell model to study the effects of lithium on OGD-PC12 cell apoptosis, autophagy and ER stress.

Results

We found that lithium administration to SCI rats reduced neuronal apoptosis and autophagy, restored rat locomotor function by reducing ER stress via IRE1 and PERK/eIF2α pathways. In vitro experiments confirmed that upon lithium treatment, OGD-PC12 cells resisted ER stress caused by thapsigargin (TG) via the IRE1 and PERK/eIF2α signaling pathways.

Conclusion

Lithium attenuated neuronal apoptosis and autophagy, and facilitates the recovery after spinal cord injury through ameliorating ER stress, providing a new therapeutic mechanism for lithium to treat SCI.

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锂通过内质网应激调节的自噬改善脊髓损伤，并通过IRE1和PERK/eIF2α信号通路减轻细胞凋亡

目的探讨锂处理脊髓损伤模型内质网(ER)应激下细胞凋亡和自噬的作用。方法建立大鼠胸10 (T10)脊髓挫伤模型，观察腹腔注射锂离子对大鼠脊髓挫伤的治疗作用。观察大鼠脊髓损伤后注射或不注射锂的组织学和行为学恢复情况。此外，我们采用氧葡萄糖剥夺(OGD)-PC12细胞模型，研究锂对OGD-PC12细胞凋亡、自噬和内质网应激的影响。结果研究发现，锂给药可通过IRE1和PERK/eIF2α通路降低内质网应激，减少脊髓损伤大鼠神经元凋亡和自噬，恢复大鼠运动功能。体外实验证实，锂处理后，OGD-PC12细胞通过IRE1和PERK/eIF2α信号通路抵抗了thapsigargin (TG)引起的内质网应激。结论锂能减轻脊髓损伤后神经元的凋亡和自噬，并通过改善内质网应激促进脊髓损伤后的恢复，为锂治疗脊髓损伤提供了一种新的治疗机制。

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