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

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 GABA_A receptors and voltage-regulated sodium channels (Na_Vs) was assessed by whole-cell patch-clamp experiments. Protection against mechanical scratch injury by CTMB or d-bicuculline, a competitive GABA_A 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 GABA_A receptors and inhibited Na_Vs, 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 Na_Vs and GABA_A 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.