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

Abstract Objectives 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 metabolomeof the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamineis protective against functional and molecular changes in diabetes. Methods We tested recognition memoryusing 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 metabolomicand 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 memoryimpairment and that this deficit was prevented by insulin or pyridoxaminetreatment. Metabolomicanalysis showed diabetes-associated changes in 13/82 identified metabolites including polyol pathwayintermediates 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 analysisrevealed 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 pyridoxamineagainst 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.