Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus
Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus
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DOI：
10.1007/s12028-016-0290-6
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Kuo, Jinn-Rung
中科院分区：
文献类型：
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作者：
Lim, Sher-Wei;Shiue, Yow-Ling;Kuo, Jinn-Rung
辛伐他汀对创伤性脑损伤(TBI)的抗抑郁作用尚不清楚。本研究旨在研究辛伐他汀的神经保护作用，并确定辛伐他汀是否能减轻脑损伤后抑郁样行为，更具体地说，是否具有抗神经炎性作用。麻醉雄性SD大鼠分为5组：假手术对照组、脑损伤对照组和脑损伤+辛伐他汀4、10、20 mg/kg治疗组。分别于伤后0、24、48h腹腔注射辛伐他汀。用斜面测量运动功能，用强迫游泳试验评估抑郁样行为。免疫荧光法检测海马CA3区小胶质细胞和星形胶质细胞的神经元凋亡(标记物：NeuN、TUNEL、caspase-3)、小胶质细胞(标记物：OX42)和星形胶质细胞(标记物：GFAP)的活化以及肿瘤坏死因子-α(TNF-α)的表达。于伤后第4、8、15天或仅在伤后第15天测定所有参数，并在伤后第15天给予辛伐他汀20 mg，可显著减轻由伤后15天引起的抑郁样行为，这种行为可延长不动时间。辛伐他汀可显著降低脑损伤后大鼠海马区CA3区小胶质细胞和星形胶质细胞的凋亡、小胶质细胞和星形胶质细胞的激活以及肿瘤坏死因子-α的表达，尤以20 mg/kg连续给药3天为甚。我们的结果表明，辛伐他汀可能是一种有前途的治疗脑损伤诱导的抑郁样行为的方法。
The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory.Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-alpha expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI.TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-alpha expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days.Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-alpha expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.