Romero Alejandro, Egea Javier, González-Muñoz Gema C, Martín de Saavedra Ma Dolores, del Barrio Laura, Rodríguez-Franco María Isabel, Conde Santiago, López Manuela G, Villarroya Mercedes, de los Ríos Cristóbal
Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
ACS Chem Neurosci. 2014 Sep 17;5(9):770-5. doi: 10.1021/cn500131t. Epub 2014 Jul 15.
The neuroprotective profile of the dibenzothiadiazepine ITH12410/SC058 (2-chloro-5,6-dihydro-5,6-diacetyldibenzo[b,f][1,4,5]thiadiazepine) against several neurotoxicity models related to neurodegenerative diseases is herein described. ITH12410/SC058 protected SH-SY5Y cells against the loss of cell viability elicited by amyloid beta peptide and okadaic acid, a selective inhibitor of phosphoprotein phosphatase 2A that induces neurofibrillary tangle formation. Furthermore, ITH12410/SC058 is neuroprotective against several in vitro models of oxidative stress, that is, H2O2 exposure or incubation with rotenone plus oligomycin A in SH-SY5Y cells, and oxygen and glucose deprivation followed by reoxygenation in rat hippocampal slices. By contrast, ITH12410/SC058 was unable to significantly protect SH-SY5Y neuroblastoma cells against the toxicity elicited by Ca(2+) overload. Our results confirm the hypothesis that the dibenzothiadiazepine ITH12410/SC058 features its neuroprotective actions in a multitarget fashion, and is a promising drug for the treatment of neurodegenerative diseases.
本文描述了二苯并噻二氮杂䓬ITH12410/SC058（2-氯-5,6-二氢-5,6-二乙酰基二苯并[b,f][1,4,5]噻二氮杂䓬）对几种与神经退行性疾病相关的神经毒性模型的神经保护作用。ITH12410/SC058保护SH-SY5Y细胞免受淀粉样β肽和冈田酸（一种诱导神经原纤维缠结形成的蛋白磷酸酶2A选择性抑制剂）引起的细胞活力丧失。此外，ITH12410/SC058对几种氧化应激体外模型具有神经保护作用，即在SH-SY5Y细胞中暴露于H2O2或与鱼藤酮加寡霉素A孵育，以及在大鼠海马切片中进行氧和葡萄糖剥夺后再给氧。相比之下，ITH12410/SC058不能显著保护SH-SY5Y神经母细胞瘤细胞免受Ca(2+)过载引起的毒性。我们的结果证实了以下假设：二苯并噻二氮杂䓬ITH12410/SC058以多靶点方式发挥其神经保护作用，是一种有前途的神经退行性疾病治疗药物。
