Protective Effects of Sulforaphane on Cognitive Impairments and AD-like Lesions in Diabetic Mice are Associated with the Upregulation of Nrf2 Transcription Activity

• Published in: Neuroscience 2018-06, Vol.381, p.35-45
• Main Authors: Pu, Die, Zhao, Yuxing, Chen, Jinliang, sun, Yue, Lv, Ankang, Zhu, Shiyu, Luo, Cheng, Zhao, Kexiang, Xiao, Qian
• Format: Article
• Language: English
• Subjects: Alzheimer Disease; Animals; Antioxidants - pharmacology; Aβ pathology; Cognitive Dysfunction - etiology; Cognitive Dysfunction - pathology; dementia; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; diabetic encephalopathy; Hippocampus - drug effects; Hippocampus - pathology; Isothiocyanates - pharmacology; Male; Mice; NF-E2-Related Factor 2 - metabolism; oxidative stress; sulforaphane; tau hyperphosphorylation; Up-Regulation
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2018.04.017

•Sulforaphane (SFN) prevents the hippocampus of T2DM mice from AD-like lesions.•This is correlated with an upregulation of Nrf2-regulated defense response to oxidative stress.•For the first time confirm the SFN protective effect on CNS in db/db mice. Type 2 diabetes mellitus (T2DM)-associated oxidative stress contributes to cognitive deficiencies and Alzheimer’s disease (AD). Sulforaphane (SFN) is a pharmacological activator of Nrf2 that provokes Nrf2-mediated intracellular defenses, including antioxidant and anti-inflammatory responses, under oxidative stress (OS) conditions. This study investigated the effects of SFN on DM-related cognitive decline and its potential mechanisms. Morris water maze (MWM) tests showed that SFN (1 mg/kg i.p. for 28 days) mitigated the cognitive decline of db/db mice, a transgenic mouse model of T2DM. Accordingly, immunoblotting and immunohistochemistry analyses showed that SFN decreased the levels of amyloid-β (Aβ) oligomers and Aβ 1–42 plaques as well as phospho-tau at Ser396 and Thr231 in the DM mouse hippocampus. This protective effect of SFN might be due to the activation of Nrf2-regulated antioxidant defense deficiencies in the DM mice, as SFN increased the Nrf2 nuclear accumulation and the downstream expression of the antioxidases HO-1 and NQO1 and reduced the levels of the reactive oxygen/nitrogen species (ROS/RNS) in DM mouse brains. Our results confirm that SFN has potential as a therapeutic agent to protect T2DM patients from cognitive deficiencies and AD-like pathological lesions related to the upregulation of Nrf2-regulated antioxidant defenses.