Yan Ruijie, Liu Qi, Zhang Di, Li Kai, Li Yue, Nie Yao, Zhang Yingying, Li Pengyu, Mao Shengjun, Li Hui
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China.
West China Medical College, Sichuan University, Chengdu, China.
Br J Pharmacol. 2025 Nov;182(21):5247-5268. doi: 10.1111/bph.70117. Epub 2025 Jun 24.
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.
Effects of a novel compound, CTMB, on both GABA receptors and voltage-regulated sodium channels (Nas) was assessed by whole-cell patch-clamp experiments. Protection against mechanical scratch injury by CTMB or d-bicuculline, a competitive GABA 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.
CTMB was an allosteric agonist at GABA receptors and inhibited Nas, 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.
Targeting both Nas and GABA 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.
创伤性脑损伤（TBI）患者中经常观察到扩散性去极化（SDs）。目前关于抑制SDs的研究主要集中在单一靶点；然而，这种方法的疗效和安全性仍存在争议。
通过全细胞膜片钳实验评估一种新型化合物CTMB对GABA受体和电压门控钠通道（Nas）的作用。使用HT22细胞培养物评估CTMB或竞争性GABA拮抗剂d - 荷包牡丹碱对机械性刮伤损伤的保护作用。在体内，于TBI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。采用蛋白质免疫印迹法、逆转录定量聚合酶链反应（RT - qPCR）和免疫组织化学分析来探究CTMB作用的潜在机制。
CTMB是GABA受体的变构激动剂并抑制Nas，从而提高SDs的阈值，并可能抑制其起始和传播。在亚急性期，CTMB恢复了兴奋与抑制之间的平衡，通过抑制线粒体相关凋亡防止神经元损伤和丢失。在恢复期，CTMB通过激活BDNF/TrkB/CREB通路促进海马体中的突触形成和突触可塑性。在TBI大鼠中，CTMB增强了神经功能，降低了癫痫发病率和死亡率，并延长了存活时间。
同时靶向Nas和GABA受体可以克服与单一靶点方法相关的局限性，为TBI药物研发提供有价值的见解和关键线索，并为涉及SDs的其他神经系统疾病（如中风和蛛网膜下腔出血）提供一种有前景的治疗策略。
