Nicotinate-curcumin ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in CA1 hippocampus
Nicotinate-curcumin ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in CA1 hippocampus
复制标题
烟酸姜黄素通过拯救 CA1 海马的自噬流改善糖尿病大鼠的认知障碍
DOI：
10.1111/cns.13059
复制
发表时间：
2019-04-01
影响因子：
5.5
通讯作者：
OuYang, Xin-Ping
中科院分区：
文献类型：
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作者：
Gu, Hong-Feng;Li, Na;OuYang, Xin-Ping
我们之前的研究证实了一种新的姜黄素衍生物烟酸-姜黄素（NC）可以促进氧化低密度脂蛋白诱导的THP-1细胞的自噬通量。鉴于自噬在神经退行性疾病中起着重要作用，本研究探讨NC是否能通过恢复CA1海马区自噬通量来改善糖尿病大鼠的认知功能。结果NC治疗可改善链脲佐菌素诱导的DM大鼠认知功能缺损，减轻CA1区神经元丢失及细胞超微结构损伤。此外，NC降低了凋亡相关蛋白Bcl-2、Bax、Cyt-c和cleaved Caspase-3的表达。值得注意的是，NC治疗逆转了DM大鼠的自噬通量损伤，这可以通过LC3-II和p62蛋白水平的降低以及海马CA1区自噬体的积累来证明。然而，NC的这些保护作用通过分别与3-甲基腺嘌呤（一种自噬抑制剂）和氯喹（一种自噬通量抑制剂）共处理而被消除。此外，NC处理降低了DM大鼠CA1区磷酸化哺乳动物雷帕霉素靶蛋白（mTOR）和p70核糖体蛋白S6激酶（p70S6k）蛋白的表达。结论NC可通过抑制CA1区mTOR/p70S6k的激活，恢复自噬通量，从而改善dm诱导的认知功能障碍，NC可能是预防和治疗糖尿病认知功能障碍的有效药物。
Introduction Our previous study has confirmed that a novel curcumin derivate nicotinate-curcumin (NC) can facilitate autophagic flux in THP-1 cells induced by oxidized low-density lipoprotein. Aims Given that autophagy plays critical roles in neurodegenerative diseases, the present study was carried out to investigate whether NC can improve cognitive function of rats with diabetes mellitus (DM) via restoring autophagic flux in CA1 hippocampus. Results Our results showed that NC treatment improved cognitive deficit and attenuated neuronal loss as well as cellular ultrastructure impairment in the CA1 region of DM rats induced by streptozotocin. Moreover, NC lowered the expressions of the apoptosis-related proteins Bcl-2, Bax, Cyt-c, and cleaved Caspase-3. Notably, NC treatment reversed autophagic flux impairment as evidenced by the deceases in LC3-II and p62 protein levels, and autophagosome accumulation in the hippocampal CA1 region of DM rats. However, these protective effects of NC were abolished by cotreatment with 3-methyladenine (an autophagy inhibitor) and chloroquine (an autophagic flux inhibitor), respectively. Furthermore, NC treatment decreased the expressions of phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase (p70S6k) proteins in the CA1 region of DM rats. Conclusions These results indicate that NC ameliorates DM-induced cognitive function impairment via restoring autophagic flux might by inhibiting mTOR/p70S6k activation in the CA1 region, and NC may be a promising agent for diabetic cognitive dysfunction prevention and treatment.