Sanz-Blasco Sara, Calvo-Rodriguez Maria, Caballero Erica, Garcia-Durillo Monica, Nunez Lucia, Villalobos Carlos
Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Spain.
Instituto de Investigaciones Farmacologicas (ININFA), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina.
Curr Alzheimer Res. 2018;15(6):504-510. doi: 10.2174/1567205015666171227154016.
Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ).
We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death.
Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.
流行病学数据表明，非甾体抗炎药（NSAIDs）可能对阿尔茨海默病（AD）具有保护作用。不幸的是，最近的试验未能提供令人信服的神经保护证据。关于NSAIDs有效性不确定的原因的讨论仍在进行中。可能的解释包括这样一种观点，即NSAIDs和其他可能的疾病修饰药物应在患者出现AD症状或认知衰退之前给予。此外，NSAIDs的神经保护靶点尚不清楚。已经提出了COX依赖性和非依赖性机制，包括切割淀粉样前体蛋白（APP）并产生淀粉样β肽（Aβ）的γ-分泌酶。
我们基于抑制线粒体Ca2+超载提出了一种NSAIDs的神经保护机制。Aβ寡聚体促进Ca2+内流和线粒体Ca2+超载，导致神经元细胞死亡。几种非特异性NSAIDs，包括布洛芬、舒林酸、吲哚美辛和氟比洛芬，在低 microM范围内使线粒体去极化，并防止由Aβ寡聚体和/或N-甲基-D-天冬氨酸（NMDA）诱导的线粒体Ca2+超载。然而，在更高浓度下，NSAIDs可能会破坏线粒体电位（ΔΨ），导致细胞死亡。
因此，这种机制可以解释低浓度时的神经保护作用和高剂量时的损伤，从而为有前景的试验失败提供线索。也许未来的试验应考虑使用更低的NSAIDs浓度和/或具有更大动态范围的替代化合物，以提供针对AD的神经保护的确切证据。
