Inhibition of spreading depolarizations by targeting GABAA receptors and voltage-gated sodium channels improves neurological deficits in rats with traumatic brain injury.

IF 7.7 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Ruijie Yan, Qi Liu, Di Zhang, Kai Li, Yue Li, Yao Nie, Yingying Zhang, Pengyu Li, Shengjun Mao, Hui Li
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Abstract

Background and purpose: Spreading depolarizations (SDs) are frequently observed in patients with traumatic brain injury (TBI). Current research on inhibiting SDs primarily focuses on single targets; however, the efficacy and safety of this approach remain controversial.

Experimental approach: Effects of a novel compound, CTMB, on both GABAA receptors and voltage-regulated sodium channels (NaVs) was assessed by whole-cell patch-clamp experiments. Protection against mechanical scratch injury by CTMB or d-bicuculline, a competitive GABAA antagonist, was assessed using cultures of HT22 cells. In vivo, short- and long-term neurobehavioural performance of male Sprague-Dawley rats were evaluated following treatment with different doses of CTMB, 2 h after TBI. Western blots, RT-qPCR and immunohistochemical assays were used to explore mechanisms underlying the effects of CTMB.

Key results: CTMB was an allosteric agonist at GABAA receptors and inhibited NaVs, thereby increasing the threshold for SDs and potentially suppressing their initiation and propagation. During the subacute phase, CTMB restored the balance between excitation and inhibition, preventing neuron injury and loss by suppressing mitochondria-involved apoptosis. In the recovery phase, CTMB promoted synaptogenesis and synaptic plasticity in the hippocampus by activating the BDNF/TrkB/CREB pathway. In TBI rats, CTMB enhanced neurological function, reducing epilepsy incidence and mortality, and prolonging survival times.

Conclusion and implications: Targeting both NaVs and GABAA receptors can overcome limitations associated with single-target approaches, providing valuable insights and critical clues for drug discovery in TBI and offering a promising therapeutic strategy for other neurological disorders involving SDs, such as stroke and subarachnoid haemorrhage.

通过靶向GABAA受体和电压门控钠通道抑制去极化扩散改善创伤性脑损伤大鼠的神经功能缺损。
背景与目的:外伤性脑损伤(TBI)患者经常观察到扩散性去极化(sd)。目前对SDs抑制的研究主要集中在单个靶点;然而,这种方法的有效性和安全性仍然存在争议。实验方法:采用全细胞膜片钳实验评估了一种新型化合物CTMB对GABAA受体和电压调节钠通道(nav)的影响。CTMB或竞争性GABAA拮抗剂d-双管碱对HT22细胞的机械划伤保护作用进行了评估。在体内,在脑外伤后2小时,用不同剂量的CTMB治疗雄性Sprague-Dawley大鼠,评估其短期和长期神经行为表现。采用Western blots、RT-qPCR和免疫组织化学方法探讨CTMB作用的机制。关键结果:CTMB是GABAA受体的变构激动剂,可抑制nav,从而提高SDs的阈值,并可能抑制其起始和繁殖。在亚急性期,CTMB恢复了兴奋和抑制之间的平衡,通过抑制线粒体相关的凋亡来防止神经元损伤和丢失。在恢复阶段,CTMB通过激活BDNF/TrkB/CREB通路促进海马突触发生和突触可塑性。在TBI大鼠中,CTMB增强神经功能,降低癫痫发病率和死亡率,延长生存时间。结论和意义:同时靶向nav和GABAA受体可以克服单靶点方法的局限性,为TBI药物开发提供有价值的见解和关键线索,并为其他涉及SDs的神经系统疾病(如中风和蛛网膜下腔出血)提供有希望的治疗策略。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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