Biochemical and functional alterations in the central and peripheral nervous system in experimental diabetes

UoM administered thesis: Phd

  • Authors:
  • Sarah Kassab

Abstract

Diabetic neuropathy (DN) is one of the most common secondary complications of diabetes mellitus principally characterised by distal nerve degeneration in the peripheral nervous system (PNS). How diabetes affects the central nervous system (CNS) is less well studied, but impairments in cognitive and psychological function in people with both type 1 and type 2 diabetes has been documented which negatively impact on quality of life and wellbeing. In this study, we describe a long-term recognition memory deficit in the streptozotocin (STZ) rat model of type 1 diabetes (8 weeks post-STZ using the novel object recognition test) that was prevented with pyridoxamine treatment (a vitamin B6 isoform). We explored the use of other ethologically-relevant assays (open-field and burrowing assays) and revealed a significant burrowing deficit which may be an indicator of overall “wellbeing” and/or affective motivation. Using comprehensive and unbiased proteomics, with bioinformatics we elucidated alterations in proteins in the hippocampus of diabetic rats compared to both control and pyridoxamine-treated diabetic rats. Proteins involved in synaptic plasticity, cytoskeletal, oxidative stress and inflammatory pathways were changed in diabetes. Untargeted metabolomics identified significant dysregulation in the hippocampus, amygdala and sciatic nerve of STZ-diabetic rats, largely in glucose metabolism and polyol pathway activation. Furthermore we showed that exogenous fructose had deleterious effects on neurite initiation, extension and survival of rat sensory neurones. Metallomics analysis however, revealed no significant changes in the levels of 22 metals studied in the PNS tissue of STZ-diabetic rats. Overall our data indicated a novel protective effect of pyridoxamine against diabetes-induced cognitive deficits highlighting its potential as a prophylactic treatment against memory impairments. Our untargeted comprehensive ‘omics data sets provide useful tools for future mechanistic and therapeutic studies on cognitive and peripheral changes in DN, and our use of ethological behavioural assays highlight the importance of implementing various assays with the ultimate aim of improving translational validity of preclinical findings and therapeutics.

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Original languageEnglish
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Award date1 Aug 2019