Inhibition of spreading depolarizations by targeting GABAA receptors and voltage-gated sodium channels improves neurological deficits in rats with traumatic brain injury.
Ruijie Yan, Qi Liu, Di Zhang, Kai Li, Yue Li, Yao Nie, Yingying Zhang, Pengyu Li, Shengjun Mao, Hui Li
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引用次数: 0
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.
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.