Longfei Li, Rugan Bao, Yao Meng, Xiaoyan Li, Hangbing Li, Pengyu Duan, Yonghong Bi, Jiali Chen, Yuling Xing, Lan Luo, Yang Yu, Miao Yu, Muyan Cui, Bing Zhang
Remimazolam attenuates neurological injury in experimental TBI and LPS/ATP-stimulated BV2 cells, partly through α7nAChR associated mitophagy enhancement and pyroptosis inhibition, while GABA_A receptor signaling may also be involved in these effects. These findings support its potential neuroprotective value in anesthesia and perioperative management.
PURPOSE: Traumatic brain injury (TBI) remains a major cause of disability and mortality worldwide. This study investigated whether remimazolam improves neurological outcomes after experimental TBI and whether these effects are associated with α7 nicotinic acetylcholine receptor (α7nAChR) related regulation of mitophagy and pyroptosis.
MATERIAL AND METHODS: Computational analyses, LPS/ATP-stimulated BV2 cells, and a mouse model of TBI were used. Molecular docking, molecular dynamics simulations, cellular thermal shift assays, and calcium influx assays were performed to evaluate the potential interaction between remimazolam and α7nAChR. Mitochondrial function, mitophagy-related markers, NLRP3, ASC, caspase-1, and GSDMD-N were assessed in BV2 cells. Neurological and behavioral outcomes were evaluated using the modified neurological severity score, rotarod test, open-field test, and novel object recognition test, together with histopathological, inflammatory, and molecular analyses of peri-lesional brain tissue. Methyllycaconitine (MLA) and flumazenil were used to assess the involvement of α7nAChR related signaling and the classical benzodiazepine sensitive GABA_A receptor pathway.
RESULTS: Remimazolam showed a predicted interaction with α7nAChR. In vitro, it enhanced mitophagy, improved mitochondrial function, and reduced the expression of NLRP3, Caspase-1, ASC, and GSDMD-N. In vivo, remimazolam improved neurological and behavioral outcomes, attenuated histopathological brain injury and neuroinflammation, promoted mitophagy and suppressed pyroptosis. MLA and flumazenil partially attenuated these protective effects.
CONCLUSION: Remimazolam attenuates neurological injury in experimental TBI and LPS/ATP-stimulated BV2 cells, partly through α7nAChR associated mitophagy enhancement and pyroptosis inhibition, while GABA_A receptor signaling may also be involved in these effects. These findings support its potential neuroprotective value in anesthesia and perioperative management.