Chlorzoxazone exhibits neuroprotection against Alzheimer's disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo
Chlorzoxazone exhibits neuroprotection against Alzheimer's disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo
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DOI：
10.1016/j.intimp.2020.106790
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发表时间：
2020-11-01
影响因子：
5.6
通讯作者：
Ma, Xinshun
中科院分区：
文献类型：
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作者：
Bai, Yanyan;Ma, Xinshun
阿尔茨海默病（AD）是一种复杂的与年龄相关的脑部疾病，是由淀粉样蛋白（a β）的积累和神经炎症引起的。氯唑唑酮（CZ）是fda批准的经典药物，具有抗炎作用。然而，到目前为止，其在AD中的调节作用尚未被研究。因此，在本研究中，我们试图探讨CZ是否可以作为一种有效的治疗AD的策略。首先，用A β模拟AD的体外研究。我们发现A β在原代小胶质细胞和星形胶质细胞中均引起p65核易位，但这种易位受到CZ处理的抑制。同时，CZ孵育可显著降低促炎细胞因子包括肿瘤坏死因子α (tnf - α)、白细胞介素-1 β (IL-1 β)的表达。在CZ处理的胶质细胞中，β沉积也明显减少。重要的是，我们发现A β诱导的胶质细胞激活及其相关的促炎症导致了明显的神经变性和神经炎症，而CZ预处理有效地减轻了离体皮质初级神经元的神经变性和神经炎症。然后，使用AD的APP/PS1小鼠进行体内研究。行为测试显示，CZ给药能有效改善AD小鼠的认知缺陷。CZ对AD小鼠海马神经元死亡也有抑制作用。cz处理的AD小鼠脑内β积累明显减少。我们最终发现，补充CZ可以明显阻断AD小鼠海马胶质细胞的激活，并显著降低tnf - α、IL-1 β和p65核易位。综上所述，CZ可以抑制神经胶质的激活和炎症反应，从而抑制神经退行性变和神经炎症。因此，CZ可能是治疗AD的有效治疗策略。
Alzheimer's disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (A beta) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using A beta. We found that A beta caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta). A beta deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by A beta led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. A beta accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-alpha, IL-1 beta and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.