Departments of Neurosurgery, The University of Texas McGovern Medical School, Houston, TX, USA.
Departments of Neurobiology and Anatomy, The University of Texas McGovern Medical School, Houston, TX, USA.
Neurochem Int. 2024 Nov;180:105874. doi: 10.1016/j.neuint.2024.105874. Epub 2024 Oct 2.
Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.
多项临床和实验研究表明，创伤性脑损伤（TBI）会激活大脑中的一系列生化、分子、结构和病理变化。这些变化共同导致 TBI 后观察到的各种结果。鉴于变化的广度和复杂性，联合治疗可能是一种针对多种有害途径的有效方法，以产生有意义的改善。为了确定治疗开发的靶点，需要在细胞和分子水平上详细阐明 TBI 的随时间演变的病理生理学，因为已经表明，导致认知功能障碍的机制会随时间而变化。因此，当基于目标细胞和分子变化的时间进程维持时，个体基于机制的治疗的联合可能是有效的。在这篇综述中，我们将讨论一些人类 TBI 的关键临床病理学的时间变化、潜在的细胞和分子机制，以及旨在减轻其后果的临床前和临床研究的结果。由于 TBI 后发生的大多数病理事件可能在疾病的慢性阶段已经消退，因此旨在减轻认知功能障碍等慢性疾病的联合治疗可能不需要在特定时间开始单独治疗。我们提出，急性、亚急性和慢性干预的联合可能是最大限度地提高 TBI 患者的健康相关生活质量（HRQoL）所必需的。
