Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (−)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (−)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.

中文翻译：

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尼伐地平通过抑制 P-SYK 抑制炎症并恢复重复性轻度 TBI 小鼠模型的空间记忆缺陷


反复接触轻度创伤性脑损伤 (mTBI) 与阿尔茨海默病 (AD)、慢性创伤性脑病 (CTE) 和其他神经退行性疾病的风险增加有关。在 TBI 和 CTE 死后大脑中发现了一些在 AD 中常见的病理特征，因此针对 AD 进行测试的治疗方法有可能有效对抗 r-mTBI 结局。神经炎症可能提供一个可能的答案，因为它在急性脑损伤和慢性退行性疾病中都发挥着核心作用。我们之前的研究表明，尼伐地平作为脾酪氨酸激酶 (SYK) 抑制剂，可有效减少 AD 小鼠模型中的炎症、tau 蛋白过度磷酸化和淀粉样蛋白的产生。为了证明尼伐地平在没有年龄相关变量的情况下的作用，我们对年轻的 r-mTBI 小鼠进行了相同的治疗。我们利用其外消旋特性进一步研究尼伐地平的治疗机制。 (+)-尼伐地平和 (−)-尼伐地平这两种对映体均可降低 SYK 活性，而 (+)-尼伐地平也是一种有效的 L 型钙通道阻滞剂 (CCB)，并具有抗高血压作用。所有 r-mTBI 小鼠均表现出神经炎症增加以及认知能力和运动功能受损。外消旋尼伐地平治疗减轻了TBI诱导的炎症反应并显着改善了空间记忆，而(−)-对映体减少了小胶质细胞增生并改善了空间记忆，但未能像外消旋体那样减少星形胶质细胞反应。这些结果表明，当与 CCB 效应相结合时，SYK 抑制的治疗潜力会增强，这表明多作用药物对 r-mTBI 的治疗优势。