Mondal Koushik, Gary Ashlyn A, Dash Anisha, Del Mar Nobel A, Stephenson Daniel J, Chalfant Charles E, Reiner Anton, Sears Barry, Mandal Nawajes
Department of Ophthalmology, The University of Health Science Centre, 930 Madison Ave., Suite 718, Memphis, TN, 38163, USA.
Molecular Diagnostics Laboratory, Department of Basic & Translational Research, Saroj Gupta Cancer Centre & Research Institute, Kolkata, WB, 700 063, India.
Mol Neurobiol. 2025 May 9. doi: 10.1007/s12035-025-05019-9.
Traumatic brain injury (TBI) causes neuroinflammation and can generate long-term pathological consequences, including motor and visual impairments, cognitive deficits, and depression. In our previous study, we found that Fat1-transgenic mice with higher endogenous n-3 polyunsaturated fatty acids (n-3 PUFA) were protected from post-TBI behavioral deficits and exhibited reduced levels of TBI-induced microglial activation, inflammatory factors, and sphingolipid ceramide, a lipid mediator of inflammation and cell death. This study's objective was to evaluate if feeding n-3 PUFA (EPA and docosahexaenoic acid, DHA 2:1) could restrict the elevation of ceramide in brain tissue and prevent TBI-mediated sensory-motor and behavioral deficits. Wildtype C57/BL6 mice were gavage pre-fed with PUFA (EPA: DHA = 2:1) at 500 mg/kg body weight/week for 2 weeks before and 4 weeks after exposure to left side focal cranial air-blast (50 psi) TBI or sham-blast (0-psi). Saline-gavaged mice served as controls. Following blast injury, various motor, visual, and behavioral tests were conducted, and brain tissues were collected for histological and biochemical assays. Lipidomics analysis confirmed a significant elevation of EPA in the plasma and brain tissue of PUFA-fed mice. TBI-Blast brain tissues were found to have elevated ceramide levels in control mice but not in PUFA-fed mice. Moreover, PUFA-fed mice demonstrated protection against motor impairment, photoreceptor dysfunction, depression, oculomotor nerve degeneration, and microglia activation in the optic tract. Our results demonstrate that EPA-mediated suppression of ceramide biosynthesis and neuroinflammatory factors in PUFA-fed mice is associated with significant protection against the visual, motor, and emotional deficits caused by TBI.
创伤性脑损伤（TBI）会引发神经炎症，并可能产生长期的病理后果，包括运动和视觉障碍、认知缺陷以及抑郁。在我们之前的研究中，我们发现内源性n-3多不饱和脂肪酸（n-3 PUFA）含量较高的Fat1转基因小鼠可免受TBI后的行为缺陷影响，并且TBI诱导的小胶质细胞激活、炎症因子和鞘脂神经酰胺（一种炎症和细胞死亡的脂质介质）水平降低。本研究的目的是评估喂食n-3 PUFA（二十碳五烯酸和二十二碳六烯酸，DHA 2:1）是否能限制脑组织中神经酰胺的升高，并预防TBI介导的感觉运动和行为缺陷。野生型C57/BL6小鼠在暴露于左侧局灶性颅脑气爆（50 psi）TBI或假气爆（0 psi）之前2周和之后4周，以500 mg/kg体重/周的剂量经口灌胃预先喂食PUFA（EPA:DHA = 2:1）。经盐水灌胃的小鼠作为对照。气爆损伤后，进行了各种运动、视觉和行为测试，并收集脑组织进行组织学和生化分析。脂质组学分析证实，喂食PUFA的小鼠血浆和脑组织中的EPA显著升高。在对照小鼠的TBI-气爆脑组织中发现神经酰胺水平升高，但在喂食PUFA的小鼠中未发现。此外，喂食PUFA的小鼠在运动障碍、光感受器功能障碍、抑郁、动眼神经变性和视束小胶质细胞激活方面表现出保护作用。我们的结果表明，喂食PUFA的小鼠中EPA介导的神经酰胺生物合成和神经炎症因子的抑制与对TBI引起的视觉、运动和情绪缺陷的显著保护有关。
