Tchantchou Flaubert, Hsia Ru-Ching, Puche Adam, Fiskum Gary
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Oncology and Diagnostic Services and Center for Innovative Biomedical Resources, University of Maryland School of Dentistry and School of Medicine, Baltimore, MD, USA.
J Cent Nerv Syst Dis. 2023 Mar 6;15:11795735231160025. doi: 10.1177/11795735231160025. eCollection 2023.
Mild traumatic brain injury (mTBI) generally resolves within weeks. However, 15-30% of patients present persistent pathological and neurobehavioral sequelae that negatively affect their quality of life. Hyperhomocysteinemia (HHCY) is a neurotoxic condition derived from homocysteine accumulation above 15 μM. HHCY can occur in diverse stressful situations, including those sustained by U.S. active-duty service members on the battlefield or during routine combat practice. Mild-TBI accounts for more than 80% of all TBI cases, and HHCY exists in 5-7% of the general population. We recently reported that moderate HHCY exacerbates mTBI-induced cortical injury pathophysiology, including increased oxidative stress. Several studies have demonstrated hippocampus vulnerability to oxidative stress and its downstream effects on inflammation and cell death.
This study aimed to assess the deleterious impact of HHCY on mTBI-associated hippocampal pathological changes. We tested the hypothesis that moderate HHCY aggravates mTBI-induced hippocampal pathological changes.
HHCY was induced in adult male Sprague-Dawley rats with a high methionine dose. Rats were then subjected to mTBI by controlled cortical impact under sustained HHCY. Blood plasma was assessed for homocysteine levels and brain tissue for markers of oxidative stress, blood-brain barrier integrity, and cell death. Endothelial cell ultrastructure was assessed by Electron Microscopy and working memory performance using the Y maze test.
HHCY increased the hippocampal expression of nitrotyrosine in astroglial cells and decreased tight junction protein occludin levels associated with the enlargement of the endothelial cell nucleus. Furthermore, HHCY altered the expression of apoptosis-regulating proteins α-ii spectrin hydrolysis, ERK1/2, and AKT phosphorylation, mirrored by exacerbated mTBI-related hippocampal neuronal loss and working memory deficits.
Our findings indicate that HHCY is an epigenetic factor that modulates mTBI pathological progression in the hippocampus and represents a putative therapeutic target for mitigating such physiological stressors that increase severity.
轻度创伤性脑损伤（mTBI）通常在数周内恢复。然而，15%至30%的患者会出现持续的病理和神经行为后遗症，对其生活质量产生负面影响。高同型半胱氨酸血症（HHCY）是一种由同型半胱氨酸积累超过15μM引起的神经毒性状态。HHCY可发生在各种应激情况下，包括美国现役军人在战场或日常战斗训练中所遭受的应激。轻度创伤性脑损伤占所有脑损伤病例的80%以上，普通人群中5%至7%存在HHCY。我们最近报告称，中度HHCY会加剧mTBI诱导的皮质损伤病理生理学，包括氧化应激增加。多项研究表明海马体易受氧化应激及其对炎症和细胞死亡的下游影响。
本研究旨在评估HHCY对mTBI相关海马体病理变化的有害影响。我们检验了中度HHCY会加重mTBI诱导的海马体病理变化这一假设。
用高剂量甲硫氨酸诱导成年雄性Sprague-Dawley大鼠出现HHCY。然后在持续HHCY状态下，通过控制性皮质撞击使大鼠遭受mTBI。检测血浆中的同型半胱氨酸水平，以及脑组织中的氧化应激标志物、血脑屏障完整性和细胞死亡情况。通过电子显微镜评估内皮细胞超微结构，并使用Y迷宫试验评估工作记忆表现。
HHCY增加了星形胶质细胞中硝基酪氨酸在海马体中的表达，并降低了与内皮细胞核增大相关的紧密连接蛋白闭合蛋白水平。此外，HHCY改变了凋亡调节蛋白α-ii血影蛋白水解、ERK1/2和AKT磷酸化的表达，这表现为mTBI相关的海马体神经元损失和工作记忆缺陷加剧。
我们的研究结果表明，HHCY是一种调节mTBI在海马体中病理进展的表观遗传因素，是减轻此类增加严重程度的生理应激源的一个假定治疗靶点。
