Sodium butyrate improves cognitive dysfunction in high-fat diet/ streptozotocin-induced type 2 diabetic mice by ameliorating hippocampal mitochondrial damage through regulating AMPK/PGC-1α pathway

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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Abstract

Cognitive dysfunction is an important comorbidity of type 2 diabetes mellitus (T2DM). Sodium butyrate (NaB) is a short-chain fatty acid and has an effect improving T2DM-associated cognitive dysfunction. Using a high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mouse model, the present study investigated the mechanism involved in the beneficial effect of butyrate on diabetic cognitive dysfunction, with a focus on ameliorating mitochondrial damage through regulating the adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α (AMPK/PGC-1α) pathway considering the important role of mitochondrial impairments in the occurrence of T2DM-associated cognitive dysfunction. We found, based on reconfirmation of the improvement of NaB on cognitive impairment, that NaB treatment improved damaged synaptic structural plasticity including the decrease in dendritic spine density and downregulation in the expression of postsynaptic density protein 95 and synaptophysin in the hippocampus in the model mice. NaB treatment also ameliorated mitochondrial ultrastructural damage, increased mitochondrial membrane potential and adenosine 5′-triphosphate content, and improved mitochondrial biogenesis and dynamics in the model mice. Furthermore, the expression of phosphorylated AMPK and PGC-1α was upregulated after NaB treatment in the model mice. In particular, the above beneficial effects of NaB were blocked by the inhibition of either AMPK or PGC-1α. In conclusion, NaB treatment improved cognitive impairment and damaged synaptic structural plasticity in the hippocampus by ameliorating damage to mitochondrial morphology and function through regulating the AMPK/PGC-1α pathway in HFD/STZ-induced T2DM mice.

丁酸钠通过调节AMPK/PGC-1α途径改善海马线粒体损伤,从而改善高脂饮食/链脲佐菌素诱导的2型糖尿病小鼠的认知功能障碍。
认知功能障碍是 2 型糖尿病(T2DM)的一个重要合并症。丁酸钠(NaB)是一种短链脂肪酸,具有改善 T2DM 相关认知功能障碍的作用。本研究利用高脂饮食(HFD)/链脲佐菌素(STZ)诱导的 T2DM 小鼠模型,探讨了丁酸钠对糖尿病认知功能障碍产生有益影响的机制、考虑到线粒体损伤在 T2DM 相关认知功能障碍发生过程中的重要作用,本研究重点探讨了通过调节单磷酸腺苷激活蛋白激酶/过氧化物酶体增殖物激活受体γ辅助激活剂 1α (AMPK/PGC-1α)通路改善线粒体损伤的机制。在再次证实 NaB 对认知障碍的改善作用的基础上,我们发现 NaB 治疗改善了模型小鼠受损的突触结构可塑性,包括树突棘密度的降低以及突触后密度蛋白 95 和突触素在海马中表达的下调。NaB 治疗还能改善线粒体超微结构损伤,提高线粒体膜电位和腺苷-5'-三磷酸含量,并改善模型小鼠线粒体的生物生成和动力学。此外,模型小鼠经 NaB 处理后,磷酸化 AMPK 和 PGC-1α 的表达得到了上调。特别是,抑制 AMPK 或 PGC-1α 可阻断 NaB 的上述有益作用。总之,NaB治疗通过调节AMPK/PGC-1α通路,改善线粒体形态和功能的损伤,从而改善HFD/STZ诱导的T2DM小鼠的认知障碍和受损的海马突触结构可塑性。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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