DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress
DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress
复制标题
DL-3-n-丁基苯酞通过增强 PI3K/Akt 信号传导和抑制氧化应激来改善糖尿病相关的认知能力下降
DOI：
10.1038/s41401-020-00583-3
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发表时间：
2021-01-18
影响因子：
8.2
通讯作者：
Wang, Jian
中科院分区：
文献类型：
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作者：
Wang, Bei-ni;Wu, Cheng-biao;Wang, Jian
DL-3-n-Butylphthalide （DL-NBP）是一种从芹菜种子中提取的小分子化合物，具有抗炎、抗氧化和抗细胞凋亡的作用，具有神经保护作用。DL-NBP不仅可以预防缺血性脑损伤，还可以改善AD、PD等痴呆患者的血管认知功能障碍。在当前的研究中，我们研究了DL-NBP是否以及如何在db/db小鼠（2型糖尿病模型）中对糖尿病相关认知能力下降（daca）发挥神经保护作用。db/db小鼠口服DL-NBP(20、60、120 mg中心点kg（-1）中心点d(-1))，持续8周。然后对小鼠进行行为学测试，采集脑组织进行形态学和生化分析。在Morris水迷宫测试中，我们发现口服DL-NBP可显著改善认知衰退，改善学习和记忆功能。此外，DL-NBP可以减轻糖尿病引起的形态学改变，增加神经元存活率，恢复突触蛋白PSD95、突触素和突触素-1水平以及海马树突密度，特别是在60 mg/kg剂量下。此外，我们发现DL-NBP通过上调Nrf2/HO-1信号来抑制氧化应激，并通过激活海马PI3K/Akt/CREB信号来增加脑源性神经营养因子（BDNF）的表达。在高糖处理的PC12细胞中观察到DL-NBP的这些有益作用。我们的研究结果表明，DL-NBP可能是一种潜在的治疗daca的药物。
DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg center dot kg(-1)center dot d(-1)) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.