Merchant Heather J, Forteath Calum, Gallagher Jennifer R, Dinkova-Kostova Albena T, Ashford Michael L J, McCrimmon Rory J, McNeilly Alison D
Division of Diabetes, Endocrinology and Reproductive Biology, School of Medicine, University of Dundee, Dundee DD1 4HN, UK.
School of Life Science, University of Dundee, Dundee DD1 4HN, UK.
Antioxidants (Basel). 2025 Mar 4;14(3):308. doi: 10.3390/antiox14030308.
In diabetes, chronic hyperglycaemia leads to cognitive impairment, neurodegeneration and dementia. In a rodent model of streptozotocin (STZ)-induced type 1 diabetes (STZ-T1D), we previously demonstrated that recurrent hypoglycaemia (RH) further exacerbates this process through a mechanism involving increased oxidative and inflammatory stress that overwhelms the compensatory activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant system, which was insufficient to prevent cognitive impairment. The current study investigated whether the induction of the antioxidant response through pre-treatment with sulforaphane (SFN), a potent Nrf2 inducer, would ameliorate these cognitive deficits. A mouse model of chronic insulin-treated T1D was achieved using STZ (125 mg/kg i.p.) and insulin implants (Linbit). Diabetic and Control (C57BL6/J) mice were randomly allocated to one of the following seven groups: (i) Control, (ii) STZ-T1D, (iii) Control + RH, (iv) STZ-T1D + RH, (v) Control + RH + SFN, (vi) STZ-T1D + RH + SFN or (vii) STZ-T1D + SFN, and subjected to insulin-induced hypoglycaemia (three episodes per week for four weeks). SFN (50 mg/kg i.p.) or a vehicle (0.1% DMSO/PBS i.p.) were administered 24 h before each hypoglycaemic episode. Cognition was assessed with the Novel Object Recognition (NOR) and spontaneous alternation (SA) tasks. SFN significantly improved the cognitive performance in the 24-h NOR and SA tasks in the STZ-T1D + RH groups. These improvements were absent in the Control or Nrf2-null mice receiving SFN. These studies show, for the first time, that the pharmacological activation of the Nrf2 antioxidant pathway may provide a novel therapeutic target for treating cognitive impairment associated with RH in T1D.
在糖尿病中，慢性高血糖会导致认知障碍、神经退行性变和痴呆。在链脲佐菌素（STZ）诱导的1型糖尿病（STZ-T1D）啮齿动物模型中，我们先前证明复发性低血糖（RH）通过一种涉及氧化应激和炎症应激增加的机制进一步加剧了这一过程，这种应激使核因子红细胞2相关因子2（Nrf2）抗氧化系统的代偿性激活不堪重负，而该系统不足以预防认知障碍。当前研究调查了用强力Nrf2诱导剂萝卜硫素（SFN）预处理诱导抗氧化反应是否能改善这些认知缺陷。使用STZ（125mg/kg腹腔注射）和胰岛素植入物（Linbit）建立了慢性胰岛素治疗的T1D小鼠模型。将糖尿病小鼠和对照（C57BL6/J）小鼠随机分为以下七组之一：（i）对照，（ii）STZ-T1D，（iii）对照+RH，（iv）STZ-T1D+RH，（v）对照+RH+SFN，（vi）STZ-T1D+RH+SFN或（vii）STZ-T1D+SFN，并使其经历胰岛素诱导的低血糖（每周三次，共四周）。在每次低血糖发作前24小时给予SFN（50mg/kg腹腔注射）或溶剂（0.1%DMSO/ PBS腹腔注射）。用新物体识别（NOR）和自发交替（SA）任务评估认知。SFN显著改善了STZ-T1D+RH组在24小时NOR和SA任务中的认知表现。在接受SFN的对照或Nrf2基因敲除小鼠中未出现这些改善。这些研究首次表明，Nrf2抗氧化途径的药理学激活可能为治疗T1D中与RH相关的认知障碍提供一个新的治疗靶点。
