Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation

Objective: The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental diabetes on the proteome and metabolome of the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamine is protective against functional and molecular changes in diabetes.Methods: We tested recognition memory using the novel object recognition (NOR) test in streptozotocin (STZ)-induced diabetic, age-matched control, and pyridoxamine- or insulin-treated diabetic male Wistar rats. Comprehensive untargeted metabolomic and proteomic analyses, using gas chromatography-mass spectrometry and iTRAQ-enabled protein quantitation respectively, were utilized to characterize the molecular changes in the hippocampus in diabetes.Results: We demonstrated diabetes-specific, long-term (but not short-term) recognition memory impairment and that this deficit was prevented by insulin or pyridoxamine treatment. Metabolomic analysis showed diabetes-associated changes in 13/82 identified metabolites including polyol pathway intermediates glucose (9.2-fold), fructose (4.9-fold) and sorbitol (5.2-fold). We identified and quantified 4807 hippocampal proteins; 806 were significantly altered in diabetes. Pathway analysis revealed significant alterations in cytoskeletal components associated with synaptic plasticity, glutamatergic signaling, oxidative stress, DNA damage and FXR/RXR activation pathways in the diabetic rat hippocampus.Conclusions: Our data indicate a protective effect of pyridoxamine against diabetes-induced cognitive deficits, and our comprehensive 'omics datasets provide insight into the pathogenesis of cognitive dysfunction enabling development of further mechanistic and therapeutic studies. (C) 2019 The Authors. Published by Elsevier GmbH.

目的：糖尿病对中枢神经系统的影响不如对周围神经系统的研究广泛，但越来越多的证据表明它会增加发生认知缺陷的风险。本研究的目的是描述实验性糖尿病对海马体蛋白质组和代谢组的影响。我们检验了维生素B6异构体吡哆胺对糖尿病的功能和分子变化具有保护作用这一假设。 方法：我们在链脲佐菌素（STZ）诱导的糖尿病雄性Wistar大鼠、年龄匹配的对照大鼠以及吡哆胺或胰岛素治疗的糖尿病大鼠中，使用新物体识别（NOR）测试来检测识别记忆。分别使用气相色谱 - 质谱法和基于iTRAQ的蛋白质定量技术进行全面的非靶向代谢组学和蛋白质组学分析，以描述糖尿病中海马体的分子变化。 结果：我们证明了糖尿病特异性的长期（而非短期）识别记忆损伤，并且这种损伤可通过胰岛素或吡哆胺治疗得以预防。代谢组学分析显示，在已鉴定的82种代谢物中有13种出现与糖尿病相关的变化，包括多元醇途径的中间产物葡萄糖（9.2倍）、果糖（4.9倍）和山梨醇（5.2倍）。我们鉴定并定量了4807种海马体蛋白质；其中806种在糖尿病中发生显著改变。通路分析显示，糖尿病大鼠海马体中与突触可塑性、谷氨酸能信号传导、氧化应激、DNA损伤以及FXR/RXR激活通路相关的细胞骨架成分发生显著改变。 结论：我们的数据表明吡哆胺对糖尿病诱导的认知缺陷具有保护作用，我们全面的“组学”数据集为认知功能障碍的发病机制提供了见解，有助于开展进一步的机制和治疗研究。（C）2019作者。由爱思唯尔股份公司出版。