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.

中文翻译：

---

高同型半胱氨酸血症引起的氧化应激会加剧大鼠皮质创伤性脑损伤的结果。


创伤性脑损伤（TBI）是美国军人和平民发病和死亡的主要原因。尽管对 TBI 病理生理学的理解取得了重大进展，但一些临床报告表明多种遗传和表观遗传因素可以影响结果。同型半胱氨酸 (HCY) 是一种非蛋白氨基酸，其分解代谢可能因压力、生活方式、衰老或遗传异常而失调，导致高同型半胱氨酸血症 (HHCY)。 HHCY 是一种神经毒性病症，也是多种神经和心血管疾病的危险因素，当临床上 HCY 水平 > 15 µM 时，就会发生这种疾病。尽管 HHCY 的有害影响已在中风、阿尔茨海默病和帕金森病等神经系统疾病的人类和动物模型中进行了研究，但尚未在 TBI 模型中得到解决。这项研究检验了 HHCY 对 TBI 病理生理学有不利影响的假设。通过每天给予蛋氨酸，然后撞击诱发创伤性脑损伤，在成年雄性 Sprague Dawley 大鼠中诱导中度 HHCY。在该模型中，HHCY 增加氧化应激，上调促进凝血的蛋白质表达，加剧 TBI 相关的血脑屏障功能障碍，并促进炎症细胞浸润到皮质。我们还观察到脑损伤引起的病变大小增加和焦虑样行为加剧。这些发现表明，中度 HHCY 会加剧 TBI 结局，并表明 HCY 分解代谢失调可能是一个重要的生物学变量，可能导致 TBI 病理生理学异质性。