The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury.
The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury.
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DOI：
10.1016/j.jss.2020.09.034
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Goodman MD
中科院分区：
文献类型：
--
作者：
Niziolek GM;Hoehn RS;Seitz AP;Jernigan PL;Makley AT;Gulbins E;Edwards MJ;Goodman MD
慢性创伤性脑病是重复性轻度创伤性脑损伤（rmTBI）的结果。这些损伤可能导致精神疾病，用阿米替林治疗。阿米替林通过抑制酸性鞘磷脂酶促进抑郁症神经元再生。我们假设，酸性鞘磷脂酶抑制剂将保留神经元再生和减少抑郁症状后rmTBI在小鼠模型。使用重量下降法建立rmTBI的鼠模型。每隔一天使小鼠经受轻度TBI，持续7天。小鼠在每次轻度TBI之前2小时接受阿米替林注射。在最终轻度TBI后，小鼠进行行为研究或生化分析。分析海马的神经发生和磷酸化tau聚集的标志物。接受rmTBI的小鼠在rmTBI后一个月表现出海马磷酸化tau蛋白聚集增加，以及通过溴脱氧尿苷摄取和双皮质素免疫组织化学减少的神经元再生。与未处理的rmTBI小鼠相比，具有酸性鞘磷脂酶的遗传缺陷或药理学抑制的小鼠表现出改善的神经元再生和减少的磷酸化tau聚集。行为测试显示，与假手术小鼠相比，rmTBI小鼠在黑暗中等待开始进食的时间明显更多。酸性鞘磷脂酶的抑制可部分阻止这些行为。我们建立了导致tau蛋白病、抑郁症和海马神经发生受损的rmTBI小鼠模型。抑制酸性鞘磷脂酶可预防rmTBI的有害神经和行为效应。这些发现强调了一个重要的机会，以改善恢复或预防慢性创伤性脑病风险患者的神经精神衰退。
Chronic traumatic encephalopathy is a consequence of repetitive mild traumatic brain injury (rmTBI). These injuries can result in psychiatric disorders that are treated with amitriptyline. Amitriptyline improves neuronal regeneration in major depression via inhibition of acid sphingomyelinase. We hypothesized that acid sphingomyelinase inhibition would preserve neuronal regeneration and decrease depressive symptoms following rmTBI in a murine model. A murine model of rmTBI was established using a weight-drop method. Mice were subjected to mild TBI every other day for 7 days. Mice received amitriptyline injection 2 hours prior to each mild TBI. After the final mild TBI, mice underwent behavioral studies or biochemical analysis. Hippocampi were analyzed for markers of neurogenesis and phosphorylated tau aggregation. Mice that underwent rmTBI showed increased hippocampal phosphorylated tau aggregation one month following rmTBI as well as decreased neuronal regeneration by bromodeoxyuridine uptake and doublecortin immunohistochemistry. Mice with either genetic deficiency or pharmacologic inhibition of acid sphingomyelinase demonstrated improved neuronal regeneration and decreased phosphorylated tau aggregation compared to untreated rmTBI mice. Behavioral testing showed rmTBI mice spent significantly more time in the dark and waiting to initiate feeding compared to sham mice. These behaviors were partially prevented by the inhibition of acid sphingomyelinase. We established a murine model of rmTBI that leads to tauopathy, depression, and impaired hippocampal neurogenesis. Inhibition of acid sphingomyelinase prevented the harmful neurologic and behavioral effects of rmTBI. These findings highlight an important opportunity to improve recovery or prevent neuropsychiatric decline in patients at risk for chronic traumatic encephalopathy.
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