Department of Anesthesiology and the Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD, 21201, USA.
Aeromedical Research, U.S Air Force School of Aerospace Medicine, Dayton, OH, USA.
Cell Mol Neurobiol. 2021 Apr;41(3):487-503. doi: 10.1007/s10571-020-00866-7. Epub 2020 May 13.
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among military service members and civilians in the United States. Despite significant advances in the understanding of TBI pathophysiology, several clinical reports indicate that multiple genetic and epigenetic factors can influence outcome. Homocysteine (HCY) is a non-proteinogenic amino acid, the catabolism of which can be dysregulated by stress, lifestyle, aging, or genetic abnormalities leading to hyperhomocysteinemia (HHCY). HHCY is a neurotoxic condition and a risk factor for multiple neurological and cardiovascular disorders that occurs when HCY levels is clinically > 15 µM. Although the deleterious impact of HHCY has been studied in human and animal models of neurological disorders such as stroke, Alzheimer's disease and Parkinson's disease, it has not been addressed in TBI models. This study tested the hypothesis that HHCY has detrimental effects on TBI pathophysiology. Moderate HHCY was induced in adult male Sprague Dawley rats via daily administration of methionine followed by impact-induced traumatic brain injury. In this model, HHCY increased oxidative stress, upregulated expression of proteins that promote blood coagulation, exacerbated TBI-associated blood-brain barrier dysfunction and promoted the infiltration of inflammatory cells into the cortex. We also observed an increase of brain injury-induced lesion size and aggravated anxiety-like behavior. These findings show that moderate HHCY exacerbates TBI outcomes and suggest that HCY catabolic dysregulation may be a significant biological variable that could contribute to TBI pathophysiology heterogeneity.
创伤性脑损伤（TBI）是美国军人和平民发病率和死亡率的主要原因。尽管人们在理解 TBI 病理生理学方面取得了重大进展，但有几项临床报告表明，多个遗传和表观遗传因素可能会影响结果。同型半胱氨酸（HCY）是一种非蛋白氨基酸，其分解代谢可以被压力、生活方式、衰老或遗传异常失调，导致高同型半胱氨酸血症（HHCY）。HHCY 是一种神经毒性状态，也是多种神经和心血管疾病的危险因素，当 HCY 水平在临床上>15 μM 时就会发生这种情况。尽管 HHCY 在中风、阿尔茨海默病和帕金森病等神经紊乱的人类和动物模型中进行了研究，但在 TBI 模型中尚未得到解决。这项研究检验了以下假设，即 HHCY 对 TBI 病理生理学有有害影响。通过每天给予蛋氨酸，在成年雄性 Sprague Dawley 大鼠中诱导中度 HHCY，然后进行撞击诱导的创伤性脑损伤。在该模型中，HHCY 增加了氧化应激，上调了促进血液凝固的蛋白质的表达，加重了与 TBI 相关的血脑屏障功能障碍，并促进了炎症细胞向皮质的浸润。我们还观察到脑损伤诱导的病变大小增加和焦虑样行为加重。这些发现表明，中度 HHCY 加重了 TBI 结局，并表明 HCY 分解代谢失调可能是导致 TBI 病理生理学异质性的重要生物学变量。
