Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive loss of cognitive functions due to neuronal death mainly in the hippocampal and cortical brain. Sulforaphene (SF) is one of the main isothiocyanates isolated from a Chinese herb Raphani Semen. In this study, we aimed to investigate the neuroprotective effects of SF using in vitro and in vivo models of AD. Streptozotocin (STZ) was intracranially injected into the rats; then, SF (25 and 50 mg/kg) was given orally once a day for 6 consecutive weeks. After drug treatment, the cognitive functions were assessed using the Morris Water Maze Test (MWMT). After the MWMT, the rats were euthanized and brain tissues were collected. In the in vitro test, BV-2 microglia were pretreated with SF (1 and 2 μM) for 1 h and then stimulated with lipopolysaccharide (LPS) for another 23 h. Both molecular and histological methods were used to unravel the action mechanisms and elucidate the signaling pathway. The MWMT results showed that SF treatment significantly improved the STZ-induced cognitive deficits in rats. SF treatment markedly suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) but increased the release of IL-10 in the STZ-treated rats. In addition, SF significantly inhibited the phosphorylation of tau protein at Thr205, Ser396, and Ser404 sites, while enhancing the ratios of p-Akt (Ser473)/Akt and p-GSK-3β (Ser9)/GSK-3β in the hippocampus of the STZ-treated rats. On the other hand, SF (1 and 2 μM) treatment also markedly attenuated the cytotoxicity induced by LPS in BV-2 cells. In addition, SF treatment obviously suppressed the releases of nitric oxide (NO), TNF-α, and IL-6 in the LPS-stimulated BV-2 cells. Moreover, SF treatment significantly mitigated the nuclear translocation of p-NF-κB p65 and the ratio of p-GSK-3β (Ser9)/GSK-3β in LPS-stimulated BV-2 cells. Taken together, SF possessed neuroprotective effects against the STZ-induced cognitive deficits in rats and LPS-induced neuroinflammation in BV-2 cells via modulation of the PI3K/Akt/GSK-3β pathway and inhibition of the NF-κB activation, suggesting that SF is a promising neuroprotective agent worthy of further development into AD treatment.

中文翻译：

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磺胺噻吩通过调节阿尔茨海默病实验模型中的PI3K / Akt /GSK-3β途径改善神经炎症和磷酸化Tau蛋白。

阿尔茨海默氏病（AD）是痴呆症的最常见形式，其特征是由于神经元死亡（主要在海马和皮层大脑中）导致的认知功能逐渐丧失。磺草芬（SF）是从中草药Raphani Semen中分离的主要异硫氰酸酯之一。在这项研究中，我们的目的是利用调查SF的保护作用在体外和体内模型AD的。颅内注射链脲佐菌素（STZ）。然后，连续6周每天一次口服SF（25和50 mg / kg）。药物治疗后，使用莫里斯水迷宫测试（MWMT）评估认知功能。MWMT后，对大鼠实施安乐死并收集脑组织。在体外测试中，BV-2小胶质细胞用SF（1和2μM）预处理 1 h，然后再用脂多糖（LPS）刺激23 h。分子和组织学方法均用于阐明作用机制并阐明信号传导途径。MWMT结果表明，SF治疗可显着改善STZ诱导的大鼠认知功能障碍。SF处理显着抑制了肿瘤坏死因子-α（TNF - α）和白介素6（IL-6）的产生，但增加了STZ处理的大鼠中IL-10的释放。此外，SF显著抑制在Thr205位，Ser396和Ser404位点的tau蛋白的磷酸化，同时增强磷酸化Akt（Ser473上）的比例/ Akt和P-GSK-3 β（Ser9）/ GSK-3 β在接受STZ治疗的大鼠的海马中。另一方面，SF（1和 2μM）处理也显着减弱了LPS在BV-2细胞中诱导的细胞毒性。此外，SF处理明显抑制了LPS刺激的BV-2细胞中一氧化氮（NO），TNF - α和IL-6的释放。此外，SF治疗显著减轻对NF-的核易位κ乙p65和P-GSK-3的比率β（Ser9）/ GSK-3 β在LPS刺激的BV-2细胞。两者合计，SF通过PI3K / AKT / GSK-3的调制具有在BV-2细胞在大鼠和LPS诱导的神经炎症对STZ诱导的认知缺陷的神经保护作用β途径和抑制NF-的κB激活，表明SF是一种有前途的神经保护剂，值得进一步发展为AD治疗。