Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent Hospital, Indianapolis, IN, USA; Departments of Neuroscience and Trauma Research, Ascension St. Vincent Hospital, Indianapolis, IN, USA; RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA.
Duke University School of Medicine, Durham, NC, USA.
Pharmacol Ther. 2024 Apr;256:108609. doi: 10.1016/j.pharmthera.2024.108609. Epub 2024 Feb 16.
Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.
创伤性脑损伤（TBI）是一种高发的医学病症，目前尚无专门用于预防或治疗该病症的药物。其症状范围包括昏迷、头痛、癫痫、认知障碍、抑郁和焦虑。尽管多年来人们已经知道抑制性神经递质γ-氨基丁酸（GABA）与 TBI 有关，但基于该机制的新型疗法尚未应用于临床实践。我们回顾了 GABA 神经传递与 TBI 的神经解剖学、神经生理学、神经化学和神经药理学关系，以期为基于 GABA 的新型药物提供新的思路。TBI 破坏兴奋性和抑制性（GABA 及其他递质）平衡的长期观点得到了实验数据的支持，但尚未发明出恢复这种平衡的新方法。在推进新疗法方面进展缓慢，是由于该疾病的复杂性，包括多个动态相互作用的生物学过程，包括血液动力学和代谢系统、神经退行性变和神经发生、神经网络和轴突的严重破坏、明显的脑损伤以及具有不同神经元和神经激素调节机制的多种症状。尽管目前和正在进行的临床研究包括 GABA 能药物，但并未探索新型 GABA 化合物。有人建议，填补理解特定神经元回路中特定 GABA 受体构型所起作用的知识空白，可能有助于确定新的治疗方法。进一步研究 GABA 调节剂的时空传递也应该是有用的。除了 GABA 调节之外，还需要研究 GABA 和非 GABA 治疗的顺序。
