Gahm C, Holmin S, Rudehill S, Mathiesen T
Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institute, Stockholm, Sweden.
Acta Neurochir (Wien). 2005 Oct;147(10):1071-84; discussion 1084. doi: 10.1007/s00701-005-0590-7. Epub 2005 Jul 29.
The pathophysiological mechanisms of secondary neurological injury after traumatic brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in brain contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine.
A brain contusion was produced using a weight-drop model in rats. The animals were treated with either one of the drugs at previously defined relevant dosage or control. Fluoro-Jade labelling, TUNEL-staining and immunohisto-chemistry were used to study neuronal degeneration, cellular apoptosis and iNOS expression. In addition, the number of surviving neurons after 14 days was determined.
The number of degenerating neurons was significantly reduced in all treatment groups at 24 hours while the total number of apoptotic cells including inflammatory cells and glia was unchanged. iNOS-expression was reduced in all treatment groups at 24 hours but not later. Only colchicine and tirilazad mesylate significantly enhanced neuronal survival at 14 days after injury.
The findings underscored that an early neuroprotective effect does not necessarily lead to increased long-term neuronal survival. The absence of a significant long-term effect with nimodipine and dexamethasone agrees with clinical studies. Colchicine with an anti-macrophage/anti-inflammatory activity and the free radical scavenger tirilazad mesylate were effective for amelioration of experimental contusion with moderate energy transfer. Early neuroprotection may to some extent target iNOS via different pathways since all tested drugs affected both iNOS expression and neuronal degeneration.
创伤性脑损伤后继发性神经损伤的病理生理机制复杂。创伤后生化反应包括实质炎症、自由基产生、细胞内钙增加、脂质过氧化和一氧化氮生成。在脑挫伤中，每种机制的相对重要性尚不清楚。本研究旨在探讨具有不同假定作用机制的神经保护和/或抗炎药物（秋水仙碱、地塞米松、甲磺酰替拉扎特和尼莫地平）的保护作用。
采用重量落体模型在大鼠中制造脑挫伤。动物接受先前确定的相关剂量的一种药物治疗或作为对照。使用荧光玉染色、TUNEL染色和免疫组织化学研究神经元变性、细胞凋亡和诱导型一氧化氮合酶（iNOS）表达。此外，还测定了14天后存活神经元的数量。
在24小时时，所有治疗组中变性神经元的数量显著减少，而包括炎性细胞和神经胶质细胞在内的凋亡细胞总数未变。在24小时时，所有治疗组中iNOS表达均降低，但之后未降低。仅秋水仙碱和甲磺酰替拉扎特在损伤后14天显著提高了神经元存活率。
研究结果强调，早期神经保护作用不一定会导致长期神经元存活率增加。尼莫地平和地塞米松缺乏显著的长期作用与临床研究结果一致。具有抗巨噬细胞/抗炎活性的秋水仙碱和自由基清除剂甲磺酰替拉扎特对中等能量传递的实验性挫伤的改善有效。早期神经保护可能在一定程度上通过不同途径靶向iNOS，因为所有测试药物均影响iNOS表达和神经元变性。
