{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:49:45Z","timestamp":1773337785315,"version":"3.50.1"},"reference-count":75,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Effects of a novel compound, CTMB, on both GABA<jats:sub>A<\/jats:sub> receptors and voltage\u2010regulated sodium channels (Na<jats:sub>V<\/jats:sub>s) was assessed by whole\u2010cell patch\u2010clamp experiments. Protection against mechanical scratch injury by CTMB or d\u2010bicuculline, a competitive GABA<jats:sub>A<\/jats:sub> antagonist, was assessed using cultures of HT22 cells. In vivo, short\u2010 and long\u2010term neurobehavioural performance of male Sprague\u2013Dawley rats were evaluated following treatment with different doses of CTMB, 2\u2009h after TBI. Western blots, RT\u2010qPCR and immunohistochemical assays were used to explore mechanisms underlying the effects of CTMB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CTMB was an allosteric agonist at GABA<jats:sub>A<\/jats:sub> receptors and inhibited Na<jats:sub>V<\/jats:sub>s, 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\u2010involved 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Targeting both Na<jats:sub>V<\/jats:sub>s and GABA<jats:sub>A<\/jats:sub> receptors can overcome limitations associated with single\u2010target 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70117","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T20:38:34Z","timestamp":1750797514000},"page":"5247-5268","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition of spreading depolarizations by targeting GABA<sub>A<\/sub> receptors and 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