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Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury
Molecular Neurobiology ( IF 4.6 ) Pub Date : 2021-08-08 , DOI: 10.1007/s12035-021-02501-y
Koushik Mondal 1 , Haruka Takahashi 1, 2 , Jerome Cole 1 , Nobel A Del Mar 3 , Chunyan Li 3 , Daniel J Stephenson 4 , Jeremy Allegood 5 , L Ashley Cowart 5, 6 , Charles E Chalfant 4, 7, 8 , Anton Reiner 1, 3 , Nawajes Mandal 1, 3, 9, 10
Affiliation  

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.



中文翻译:

n-3 多不饱和脂肪酸 (n-3-PUFA) 的全身升高与保护小鼠在闭头轻度创伤性脑损伤后的视觉、运动和情绪缺陷有关

创伤性脑损伤 (TBI) 会导致神经炎症和神经变性,从而导致各种病理并发症,例如运动和感觉(视觉)缺陷、认知障碍和抑郁症。已知含有 N-3 多不饱和脂肪酸 (n-3 PUFA) 的脂质具有抗炎作用,而鞘脂、神经酰胺 (Cer) 是神经炎症和变性的诱导剂。使用含有升高水平的全身 n-3 PUFA 的Fat1 + -转基因小鼠,我们通过对Fat1进行测试来测试它们是否能够抵抗轻度 TBI 介导的感觉运动和情绪缺陷。-转基因小鼠及其 WT 同窝小鼠进行局灶性颅内空气冲击 (50 psi) 或假冲击 (0 psi, 对照)。我们观察到 WT 小鼠的视觉功能在 TBI 后显着降低,但在Fat1 + -blast 动物中没有。我们还发现了Fat1 +-blast 小鼠对爆炸的运动功能、抑郁和恐惧产生效应的下降具有抵抗力,以及在 WT 爆炸后观察到的脑切片中动眼神经核面积的减少和视束中活化小胶质细胞的增加老鼠。脂质和基因表达分析证实血浆和脑中 n-3 PUFA 二十碳五烯酸 (EPA) 水平升高,阻断 TBI 介导的脑中 Cer 增加,以及 TBI 介导的 Cer 生物合成和炎症诱导减少Fat1 +小鼠大脑中的基因表达。我们的研究结果表明,抑制Fat1 +中的神经酰胺生物合成和炎症因子-转基因小鼠与对轻度 TBI 引起的视觉、运动和情绪缺陷的显着保护有关。这项研究表明,n-3 PUFA(尤其是 EPA)在预防 TBI 后的神经退行性变方面具有很有前景的治疗作用。

更新日期:2021-08-10
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