Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway
Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway
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DOI：
10.1007/s12035-015-9451-4
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发表时间：
2016-10-01
影响因子：
5.1
通讯作者：
Shukla, Rakesh
中科院分区：
文献类型：
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作者：
Dwivedi, Subhash;Rajasekar, N.;Shukla, Rakesh
冈田酸（OKA）导致记忆障碍，并减弱核因子红细胞2相关因子2（Nrf 2）沿着氧化应激和神经炎症。萝卜硫素（膳食异硫氰酸酯化合物）是Nrf 2信号传导的激活剂，具有神经保护作用。然而，萝卜硫素在OKA诱导的神经毒性中的保护作用尚未研究。因此，在本研究中，萝卜硫素在OKA诱导的大鼠记忆障碍中的作用进行了探讨。在训练的（Morris水迷宫）大鼠中观察到海马和大脑皮质中Nrf 2表达显著增加，而在记忆受损（OKA，200 ng icv）大鼠中Nrf 2表达显著降低，表明其参与记忆功能。萝卜硫素给药（5和10 mg/kg，ip，第1和2天）改善OKA诱导的大鼠记忆障碍。治疗还恢复了Nrf 2及其下游抗氧化蛋白（GCLC，HO-1）的表达，并减弱了OKA治疗大鼠大脑皮层和海马中的氧化应激（ROS，亚硝酸盐，GSH），神经炎症（NF-κ B，TNF-α，IL-10）和神经元凋亡。此外，为了确定Nrf 2信号传导的调节是否负责萝卜硫素的保护作用，在体外，在大鼠星形细胞瘤细胞系（C6）中进行Nrf 2 siRNA及其下游HO-1抑制研究。抑制星形胶质细胞中的Nrf 2 siRNA和HO-1可消除萝卜硫素的保护作用。结果表明，Nrf 2依赖性激活的细胞抗氧化机制的结果在萝卜硫素介导的保护OKA诱导的记忆障碍大鼠。
Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA-induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-kappa B, TNF-alpha, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA-induced memory impairment in rats.