中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (8): 2325-2336.doi: 10.4103/NRR.NRR-D-23-01424

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

盐酸羟哌吡酮YL-0919改善创伤性脑损伤小鼠功能障碍的抗氧化作用

  

  • 出版日期:2025-08-15 发布日期:2024-12-13

Hypidone hydrochloride (YL-0919) ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Yafan Bai1, #, Hui Ma2, #, Yue Zhang1, #, Jinfeng Li2 , Xiaojuan Hou3 , Yixin Yang2 , Guyan Wang1, *, Yunfeng Li2, 4, *   

  1. 1 Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China;  2 Beijing Institute of Basic Medical Sciences, Beijing, China;  3 Hebei North University, Zhangjiakou, Hebei Province, China;  4 Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, China
  • Online:2025-08-15 Published:2024-12-13
  • Contact: Yunfeng Li, PhD, PharmD, lyf619@aliyun.com; Guyan Wang, PhD, MD, guyanwang2006@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82204360 (to HM) and 82270411 (to GW); National Science and Technology Innovation 2030 Major Program, No. 2021ZD0200900 (to YL).

摘要:

创伤性脑损伤涉及复杂的机制,其中氧化应激在很大程度上导致了继发性损伤的发生。盐酸羟哌吡酮YL-0919是一种自主研发的抗抑郁药,具有选择性Sigma-1 受体(σ-1R)激动剂的特性,为了评估它对创伤性脑损伤的相关机制和作用靶点。实验首先进行了行为实验,评估功能障碍。随后,通过组织学分析评估了神经元损伤,并检测了血脑屏障(BBB)的通透性和脑水肿。接下来,实验通过评估体内和体外氧化应激的传统标志物水平,研究了YL-0919的抗氧化作用。最后,通过使用σ-1R拮抗剂BD-1047验证了YL-0919的作用靶点。结果显示,YL-0919可显著改善创伤性脑损伤后第 3 天的运动功能和空间认知障碍,同时还能降低神经元死亡率,逆转血脑屏障破坏和脑水肿。此外,YL-0919 还能有效抑制体内和体外氧化应激。BD-1047 部分抑制了 YL-0919 的保护作用。这些结果表明,YL-0919通过抑制氧化应激缓解了运动和空间认知障碍,其神经保护作用可被σ-1R拮抗剂BD-1047部分逆转。因此,YL-0919可以作为一种治疗创伤性脑损伤的有前途新疗法。

https://orcid.org/0000-0002-9696-890X (Yunfeng Li); https://orcid.org/0000-0001-6957-6356 (Guyan Wang)

Abstract: Traumatic brain injury involves complex pathophysiological mechanisms, among which oxidative stress significantly contributes to the occurrence of secondary injury. In this study, we evaluated hypidone hydrochloride (YL-0919), a self-developed antidepressant with selective sigma-1 receptor agonist properties, and its associated mechanisms and targets in traumatic brain injury. Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema. Next, we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells. Finally, the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist (BD-1047). Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury, while also decreasing neuronal mortality and reversing blood–brain barrier disruption and brain edema. Furthermore, YL-0919 effectively combated oxidative stress both in vivo and in vitro. The protective effects of YL-0919 were partially inhibited by BD-1047. These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress, a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047. YL-0919 may have potential as a new treatment for traumatic brain injury.

Key words: antidepressant drug, blood–brain barrier, cognitive function, hypidone hydrochloride (YL-0919), neurological function, nuclear factor-erythroid 2 related factor 2, oxidative stress, sigma-1 receptor, superoxide dismutase, traumatic brain injury