Pedersen Mie Ø, Larsen Agnete, Stoltenberg Meredin, Penkowa Milena
Section of Neuroprotection, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Prog Histochem Cytochem. 2009;44(1):1-27. doi: 10.1016/j.proghi.2008.10.002. Epub 2008 Dec 2.
In traumatic brain injury (TBI), the primary, irreversible damage associated with the moment of impact consists of cells dying from necrosis. This contributes to fuelling a chronic central nervous system (CNS) inflammation with increased formation of proinflammatory cytokines, enzymes and reactive oxygen species (ROS). ROS promote oxidative stress, which leads to neurodegeneration and ultimately results in programmed cell death (secondary injury). Since this delayed, secondary tissue loss occurs days to months following the primary injury it provides a therapeutic window where potential neuroprotective treatment could alleviate ongoing neurodegeneration, cell death and neurological impairment following TBI. Various neuroprotective drug candidates have been described, tested and proven effective in pre-clinical studies, including glutamate receptor antagonists, calcium-channel blockers, and caspase inhibitors. However, most of the scientific efforts have failed in translating the experimental results into clinical trials. Despite intensive research, effective neuroprotective therapies are lacking in the clinic, and TBI continues to be a major cause of morbidity and mortality. This paper provides an overview of the TBI pathophysiology leading to cell death and neurological impairment. We also discuss endogenously expressed neuroprotectants and drug candidates, which at this stage may still hold the potential for treating brain injured patients.
在创伤性脑损伤（TBI）中，与撞击瞬间相关的原发性、不可逆损伤包括因坏死而死亡的细胞。这会助长慢性中枢神经系统（CNS）炎症，促炎细胞因子、酶和活性氧（ROS）的形成增加。ROS会引发氧化应激，导致神经退行性变，并最终导致程序性细胞死亡（继发性损伤）。由于这种延迟的继发性组织损失发生在原发性损伤后的数天至数月，因此提供了一个治疗窗口，在此期间潜在的神经保护治疗可以减轻TBI后持续的神经退行性变、细胞死亡和神经功能障碍。各种神经保护候选药物已在临床前研究中得到描述、测试并证明有效，包括谷氨酸受体拮抗剂、钙通道阻滞剂和半胱天冬酶抑制剂。然而，大多数科学努力在将实验结果转化为临床试验方面都失败了。尽管进行了深入研究，但临床上仍缺乏有效的神经保护疗法，TBI仍然是发病和死亡的主要原因。本文概述了导致细胞死亡和神经功能障碍的TBI病理生理学。我们还讨论了内源性表达的神经保护剂和候选药物，在现阶段它们仍可能具有治疗脑损伤患者的潜力。
