Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer's disease via activation of Nrf2/ARE pathway and inhibition of β-secretase
Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer's disease via activation of Nrf2/ARE pathway and inhibition of β-secretase
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DOI：
10.1016/j.biopha.2018.02.052
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发表时间：
2018-05-01
影响因子：
7.5
通讯作者：
Kokare, Dadasaheb M.
中科院分区：
文献类型：
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作者：
Nakhate, Kartik T.;Bharne, Ashish P.;Kokare, Dadasaheb M.
尽管白丹素（5-羟基-2-甲基-1,4-萘醌）通过激活核因子-红细胞2相关因子-2/抗氧化反应元件（Nrf2/ARE）通路，对脑缺血和脊髓损伤诱导的氧化应激和炎症具有保护作用，但其在改善神经退行性疾病中的作用尚不清楚。在本研究中，我们研究了白桦素对小鼠阿尔茨海默病（AD）样疾病的影响。采用链脲佐菌素（STZ, 3mg /kg）脑室内灌胃治疗，第1天和第3天诱导ad样症状，第14天评价症状。虽然莫里斯水迷宫（MWM）小鼠的学习和记忆能力明显下降，但海马中标记有胶质纤维酸性蛋白（GFAP）的星形胶质细胞数量显著增加。从首次给药前1小时开始，每天腹腔注射白桦素（0.5和1 mg/kg），可显著预防MWM患者的认知功能障碍。另一方面，给予Nrf2/ARE通路抑制剂葫芦巴碱（10和15 mg/kg， ig）可增强STZ的作用。用亚有效剂量的葫芦巴碱（5 mg/kg）预处理可显著减弱白桦素对MWM的作用。白丹素能抑制STZ诱导的GFAP表达，但葫芦巴碱能减弱白丹素的抑制作用。此外，硅对接研究表明，白桦素对β -分泌酶有明显的抑制作用。本研究结果提示，白桦素改善STZ诱导的AD小鼠模型的认知功能可能通过Nrf2/ARE介导的星形胶质细胞增生的抑制和β -分泌酶的抑制。
Although plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) protects against cerebral ischemia and spinal cord injury-induced oxidative stress and inflammation by activating the nuclear factor-erythroid 2-related factor-2/antioxidant response element (Nrf2/ARE) pathway, its role in the amelioration of neurodegenerative diseases remains unexplored. In the present study, we investigated the effect of plumbagin on Alzheimer's disease (AD)-like condition in mice. The animals were treated intracerebroventricularly with streptozotocin (STZ; 3 mg/kg) twice, on day 1 and 3, to induce AD-like condition, and the symptoms were evaluated after 14 days. While the loss of learning and memory performance was evident in the mice subjected to Morris water maze (MWM), there was a striking increase in the population of astrocytes labelled with glial fibrillary acidic protein (GFAP) in the hippocampus. Daily intraperitoneal (i.p.) treatment with plumbagin (0.5 and 1 mg/kg), starting from 1 h prior to first dose of STZ, significantly prevented the cognitive deficits in MWM. On the other hand, administration of Nrf2/ARE pathway inhibitor, trigonelline (10 and 15 mg/kg, i.p.) enhanced the effects of STZ. Pre-treatment with subeffective dose of trigonelline (5 mg/kg) significantly attenuated the effects of plumbagin in MWM. While plumbagin prevented the STZ induced GFAP expression, this effect of plumbagin was attenuated by trigonelline. Moreover, the in silico docking study revealed potent inhibitory effect of plumbagin on beta-secretase enzyme. The results of the present study suggest that plumbagin improves cognitive function in STZ induced mouse model of AD possibly via Nrf2/ARE mediated suppression of astrogliosis and inhibition of beta-secretase enzyme.