Microglial KCa3.1 Channels as a Potential Therapeutic Target for Alzheimer's Disease.
Microglial KCa3.1 Channels as a Potential Therapeutic Target for Alzheimer's Disease.
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DOI：
10.1155/2012/868972
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发表时间：
2012
影响因子：
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通讯作者：
Wulff H
中科院分区：
文献类型：
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作者：
Maezawa I;Jenkins DP;Jin BE;Wulff H
目前迫切需要发现治疗阿尔茨海默病（AD）的新靶点；然而，最近基于抗a β和抗炎策略的临床试验产生了令人失望的结果。为了加速新药的发现，我们建议重新定位工业界和学术界以前追求的适应症，以用于AD以外的适应症。其中一个靶点是钙活化钾通道KCa3.1 (KCNN4)，它在大脑中主要在小胶质细胞中表达，当小胶质细胞被激活时，它会显著上调。我们在此回顾了现有的证据，支持KCa3.1抑制可以阻断小胶质神经毒性，而不影响其神经保护性吞噬活性，也不会产生广泛的免疫抑制。KCa3.1阻断剂的抗炎和神经保护作用适用于AD以及脑血管和外伤性脑损伤，这两个众所周知的导致AD患者痴呆的危险因素表现为混合病理。重要的是，几种KCa3.1阻滞剂的药代动力学和药效学是已知的，并且一种KCa3.1阻滞剂已在临床试验中被证明是安全的。因此，在AD临床前和临床试验中重新定位旧的或新的KCa3.1阻滞剂是有希望的。
There exists an urgent need for new target discovery to treat Alzheimer's disease (AD); however, recent clinical trials based on anti-Aβ and anti-inflammatory strategies have yielded disappointing results. To expedite new drug discovery, we propose reposition targets which have been previously pursued by both industry and academia for indications other than AD. One such target is the calcium-activated potassium channel KCa3.1 (KCNN4), which in the brain is primarily expressed in microglia and is significantly upregulated when microglia are activated. We here review the existing evidence supporting that KCa3.1 inhibition could block microglial neurotoxicity without affecting their neuroprotective phagocytosis activity and without being broadly immunosuppressive. The anti-inflammatory and neuroprotective effects of KCa3.1 blockade would be suitable for treating AD as well as cerebrovascular and traumatic brain injuries, two well-known risk factors contributing to the dementia in AD patients presenting with mixed pathologies. Importantly, the pharmacokinetics and pharmacodynamics of several KCa3.1 blockers are well known, and a KCa3.1 blocker has been proven safe in clinical trials. It is therefore promising to reposition old or new KCa3.1 blockers for AD preclinical and clinical trials.