Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, One Children's Place, St. Louis, MO 63110, USA.
Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, One Children's Place, St. Louis, MO 63110, USA.
Exp Neurol. 2021 Jan;335:113507. doi: 10.1016/j.expneurol.2020.113507. Epub 2020 Oct 13.
Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain's resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes.
创伤性脑损伤 (TBI) 神经保护剂的临床前研究表明，在实验性 TBI 之前或非常早期给予治疗时具有前景。然而，在人类中，具有 TBI 临床前疗效的治疗方法的临床试验未能复制这些结果，这是一种转化失败的现象。N-乙酰半胱氨酸 (NAC) 是一种有效的抗氧化剂，在初级损伤后早期给予时，在临床前 TBI 中显示出疗效。利用我们具有临床相关性的小鼠模型，我们假设在临床相关时间范围内给予 NAC 可以提高大脑对缺氧性二次损伤的抵抗力。在雄性小鼠中，在缺氧（控制性皮质撞击后 24 小时）之前 2 小时开始每天给予 NAC 或载体，共 3 剂，可减少短期轴突损伤和海马神经元丢失。6 个月的行为评估，包括新物体识别、社交、巴恩斯迷宫和恐惧条件反射，未显示接受 NAC 或生理盐水载体的受伤小鼠与假手术对照之间的性能差异。在受伤后 7 个月时，给予 NAC 的小鼠海马神经元丢失减少，但病变体积没有减少。总之，我们进行的这项临床前试验旨在测试 NAC 对 TBI 后二次缺氧性损伤的神经保护作用，结果表明 NAC 具有短期和长期神经病理学神经保护作用，但在假手术对照和受伤小鼠之间的长期行为评估中未发现可检测到的差异，限制了对其对长期神经行为结果影响的结论。
