Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
Diabetes. 2020 Jul;69(7):1411-1423. doi: 10.2337/db19-1128. Epub 2020 Apr 28.
Previous studies showed that 12 weeks of high-fat diet (HFD) consumption caused not only prediabetes but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats ( = 32) were fed with either normal diet (ND) or HFD for 20 weeks. At week 13, ND-fed rats were given a vehicle ( = 8) and HFD-fed rats were randomly assigned into three subgroups ( = 8/subgroup) with vehicle, nec-1, or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer protein, and cell death were determined. HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, and brain mitochondrial function and reduced hyperphosphorylated Tau and necroptosis in HFD-fed rats. Interestingly, metformin, but not nec-1, improved brain insulin sensitivity in those rats. In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity.
先前的研究表明，12 周的高脂肪饮食（HFD）不仅会导致糖尿病前期，还会导致认知能力下降和大脑病理变化。最近，坏死性凋亡抑制剂 necrostatin-1（nec-1）在对抗中风方面对大脑有有益的影响。然而，nec-1 和二甲双胍对糖尿病前期认知和大脑病理的比较影响尚未得到研究。我们假设 nec-1 和二甲双胍对糖尿病前期大鼠的认知能力下降和大脑病理有同等的缓解作用。将大鼠（=32 只）分为正常饮食（ND）组或 HFD 组喂养 20 周。在第 13 周，ND 喂养的大鼠给予载体（=8 只），HFD 喂养的大鼠随机分为三组（=8/组），分别给予载体、nec-1 或二甲双胍治疗 8 周。测定代谢参数、认知功能、脑胰岛素受体功能、突触可塑性、树突棘密度、小胶质细胞形态、脑线粒体功能、阿尔茨海默病蛋白和细胞死亡。HFD 喂养的大鼠出现糖尿病前期、认知能力下降和大脑病理变化。Nec-1 和二甲双胍同样改善了 HFD 喂养大鼠的认知功能、突触可塑性、树突棘密度、小胶质细胞形态和脑线粒体功能，并减少了 HFD 喂养大鼠中磷酸化 Tau 和坏死性凋亡。有趣的是，只有二甲双胍而不是 nec-1 改善了这些大鼠的脑胰岛素敏感性。总之，坏死性凋亡抑制直接改善了糖尿病前期大鼠的认知能力，而不改变胰岛素敏感性。
