Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI.
Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI.
复制标题
DOI：
10.1186/s40478-020-01045-x
复制
发表时间：
2020-10-19
影响因子：
7.1
通讯作者：
Crawford F
中科院分区：
文献类型：
--
作者：
Morin A;Mouzon B;Ferguson S;Paris D;Browning M;Stewart W;Mullan M;Crawford F
反复暴露于轻度脑损伤(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。在颅脑损伤和CTE的死后脑中发现了一些在AD中观察到的典型病理特征，因此测试的AD治疗方法有可能有效地对抗r-mTBI的结果。神经炎可能提供了一个可能的答案，因为它在急性脑损伤和慢性退行性疾病中都发挥了核心作用。我们以前的研究表明，药物尼伐地平作为脾酪氨酸激酶(SYK)的抑制剂，可以有效地减少AD模型小鼠的炎症、tau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效果，我们对年轻的r-mTBI小鼠进行了同样的治疗。我们利用尼伐地平的外消旋特性进一步探讨了其治疗机制。两种对映体(+)-尼伐地平和(−)-尼伐地平均能降低SYK活性，而(+)-尼伐地平也是一种有效的L型钙通道阻滞剂，具有降压作用。所有r-mTBI小鼠都表现出神经炎症增加，认知能力和运动功能受损。尼伐地平外消旋治疗减轻了脑挫伤所致的炎症反应，显著改善了空间记忆，而(−)对映体减少了小胶质细胞的形成，改善了空间记忆，但不能降低星形胶质细胞对消旋体的反应。这些结果提示SYK抑制的治疗潜力在与CCB效应相结合时被增强，这表明多作用药物对r-mTBI具有治疗优势。本文的在线版本(10.1186/s40478-020-020-x)包含向授权用户提供的补充材料。
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. The online version of this article (10.1186/s40478-020-01045-x) contains supplementary material, which is available to authorized users.
登录
查看更多内容
重复性轻度创伤性脑损伤的终生行为和神经病理学后果。
影响因子：
5.3
作者：
Mouzon BC;Bachmeier C;Ojo JO;Acker CM;Ferguson S;Paris D;Ait-Ghezala G;Crynen G;Davies P;Mullan M;Stewart W;Crawford F
通讯作者：
Crawford F
影响因子：
2.7
作者：
Jordan, BD
通讯作者：
Jordan, BD
影响因子：
4
作者：
Hanyu, Haruo;Hirao, Kentaro;Iwamoto, Toshihiko
通讯作者：
Iwamoto, Toshihiko
影响因子：
4
作者：
Kennelly, S. P.;Abdullah, L.;Kenny, R. A.
通讯作者：
Kenny, R. A.
影响因子：
158.5
作者：
Mackay, Daniel F.;Russell, Emma R.;Stewart, William
通讯作者：
Stewart, William