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Otilonium and pinaverium trigger mitochondrial-mediated apoptosis in rat embryo cortical neurons in vitro
NeuroToxicology ( IF 3.4 ) Pub Date : 2018-11-15 , DOI: 10.1016/j.neuro.2018.11.003
Fernanda García-Alvarado , Giulia Govoni , Ricardo de Pascual , Cristina Ruiz-Ruiz , Alicia Muñoz-Montero , Luis Gandía , Antonio M.G de Diego , Antonio G. García

In the frame of a repositioning programme with cholinergic medicines in clinical use searching for neuroprotective properties, we surprisingly found that spasmolytic antimuscarinics otilonium and pinaverium exhibited neurotoxic effects in neuronal cultures. We decided to characterize such unexpected action in primary cultures of rat embryo cortical neurons. Neurotoxicity was time- and concentration-dependent, exhibiting approximate EC50 values of 5 μM for both drugs. Seven antimuscarinic drugs endowed with a quaternary ammonium, and another 10 drugs with different cholinergic activities, carrying in their molecule a ternary ammonium did not exhibit neurotoxicity. Both drugs caused a concentration-dependent blockade of whole-cell inward currents through voltage-activated calcium channels (VACCs). Consistent with this, they also blocked the K+-elicited [Ca2+]c transients. Neither antioxidant catalase, glutathione, n-acetylcysteine, nor melatonin protected against neurotoxicity of otilonium or pinaverium. However cyclosporine A, a blocker of the mitochondrial permeability transition pore, prevented the neurotoxic effects of otilonium and pinaverium monitored as the fraction of cells undergoing apoptosis. Furthermore, the caspase-9 and caspase-3 inhibitor Ac-LEHD-CHO mitigated the apoptotic neuronal death of both drugs by around 50%. Data are compatible with the hypothesis that otilonium and pinaverium elicit neuronal death by activating the intrinsic mitochondrial-mediated signaling pathway of apoptosis. This may have its origin in the mitigation of Ca2+ entry and the uncoupling of the Ca2+-dependent generation of mitochondrial bioenergetics, thus causing the opening of the mitochondrial mPTP to elicit apoptotic neuronal death.



中文翻译:

til和pin虫触发线粒体介导的大鼠胚胎皮层神经元凋亡

在临床使用胆碱能药物的重新定位程序的框架中,以寻找神经保护特性,我们意外地发现,痉挛性抗毒蕈碱奥替隆和吡那韦在神经元培养物中表现出神经毒性作用。我们决定在大鼠胚胎皮层神经元的原代培养中表征这种出乎意料的作用。神经毒性取决于时间和浓度,表现出大约EC 50两种药物的5μM值。七种抗毒蕈碱药物具有季铵盐,另外十种具有不同胆碱能活性的药物在其分子中带有三元铵盐并没有表现出神经毒性。两种药物都通过电压激活钙通道(VACC)引起全细胞内向电流的浓度依赖性阻断。与此相一致,他们还阻断了由K +引起的[Ca 2+ ] c瞬变。抗氧化剂过氧化氢酶,谷胱甘肽,正乙酰半胱氨酸和褪黑激素都不能防止奥替隆或吡那韦的神经毒性。然而,环孢素A是线粒体通透性过渡孔的阻滞剂,它可以阻止被监测的细胞凋亡的比例,从而检测到otilonium和pinaverium的神经毒性作用。此外,caspase-9和caspase-3抑制剂Ac-LEHD-CHO使两种药物的凋亡神经元死亡减轻了约50%。数据与以下假设相符,即烯和pin藜芦通过激活内在的线粒体介导的细胞凋亡信号传导途径引起神经元死亡。这可能起源于Ca的缓解2+条目和钙的解偶联2+依赖的线粒体生物能产生,从而导致线粒体mPTP的开放引发凋亡性神经元死亡。

更新日期:2018-11-15
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