Decreased amino acids in the brain might contribute to the progression of diabetic neuropathic pain

https://doi.org/10.1016/j.diabres.2021.108790Get rights and content

Highlights

  • Metabolites in the brain were dynamically changed during the progression of DNP.

  • The brain metabolites altered over the progression of DNP were mainly amino acids.

  • Amino acid precursors of analgesic neurotransmitters decreased over DNP progression.

Abstract

Aims

The pathophysiological alteration of diabetic neuropathic pain (DNP) in brain is unclear. Here we aimed to explore the metabolomic characteristics of brain in rats over the progression of DNP through metabolomic analysis.

Methods

Adult rats were randomly divided into control group and DNP group. Body weight, blood glucose and behavioral assessment of neuropathic pain were measured every week after streptozotocin (STZ) injection. Finally, the brains of 2 rats from control group and 6 rats from DNP group were removed every 4 weeks after STZ injection for metabolomics analysis.

Results

After 4 weeks of STZ-injection, the rats with diabetes developed DNP, which was characterized as mechanical allodynia and thermal nociception. As for metabolomic analysis, differentially expressed metabolites (DE metabolites) showed a dynamic alteration over the development of DNP and affected several KEGG pathways associated with amino acid metabolism. Furthermore, the expression of l-Threonine, l-Methionine, d-Proline, l-Lysine and N-Acetyl-l-alanine were significantly decreased at all time points of DNP group. The amino acids which were precursor of analgesic neurotransmitters were downregulated over the progression of DNP, including l-tryptophan, l-histidine and l-tyrosine.

Conclusions

The impairment of amino acid metabolism in brain might contribute to the progression of DNP through decreasing analgesic neurotransmitters.

Introduction

Diabetic peripheral neuropathy is one of the most frequent complications of diabetes mellitus (DM) [1], and approximately 61.8% of patients with DM develop diabetic peripheral neuropathy [2]. Up to 25% of patients with diabetic peripheral neuropathy develop diabetic neuropathic pain (DNP) [3], which is characterized by spontaneous pain, hyperalgesia, and allodynia. Compared with painless diabetic neuropathy, DNP significantly decreases the quality of life of patients with issues such as depression, anxiety, sleep disturbances, and reduced employability at work [4], [5], [6]. Therefore, understanding the pathophysiology and potential mechanisms of DNP is important to improve the treatment and management of DNP.

The pathophysiology of DNP is complex and multifactorial; it includes peripheral mechanisms and central mechanisms [7]. In recent years, an increasing number of studies have focused on the role of the central nervous system (CNS) in DNP. Central sensitization increased thalamic vascularity, and changes in the balance of facilitation and inhibition within the descending pathways have been reported as the central mechanisms of DNP [7]. However, the crossover and interaction between these central pathways in DNP are unclear and can be approached by omics technologies. Metabolomics is a powerful tool to reveal the metabolic changes and potential mechanisms involved in the pathogenesis of DNP. Several studies have investigated the metabolomic signature of the peripheral nervous system in diabetes, such as the upregulation of mitochondrial oxidative phosphorylation, the perturbation of the lipid metabolism, the dysregulation of the tricarboxylic acid (TCA) cycle, and glycolysis [8], [9], [10]. However, the metabolomics characteristics of the CNS in DNP have not yet been reported.

In the present study, through metabolomic analysis, we aimed to explore the metabolomic characteristics of the brain in rats during the progression of DNP. The metabolomic analysis used in the present study provides novel insights into the pathogenesis of DNP and enables the generation of new therapeutic targets.

Section snippets

Animals

Adult male Sprague-Dawley rats (weight 160–180 g, aged 5–6 weeks) were purchased from the Shanghai Laboratory Animal Center. All rats were housed in a temperature- and humidity-controlled environment and were fed food and water ad libitum. The animal protocols were approved by the Animal Care and Welfare Committee of Fudan University.

All rats were acclimated to the housing environment for 2 weeks (weighing approximately 250 g, aged 7–8 weeks) and were randomly assigned to the control group (CON

Characteristics of STZ-induced diabetic rats over time

This study investigated the metabolic alterations occurring in brain over the course of progression of DNP. After 72 h of STZ-injection, the rats in DNP group developed hyperglycemia and showed significantly higher blood glucose compared with CON group from 1 week onwards post-STZ injection over the entire course of study (P < 0.0001) (Fig. 1A). STZ-injected rats did not only suffer any weight loss but also not gain weight as age progressed, unlike age-matched controls at all time points (P

Discussion

DNP is the major cause of poor quality of life in patients with diabetes. The brain is the integration center of pain and plays a crucial role in the development of DNP. As the development of DNP is a continuous and dynamic process, we aimed to explore the temporal metabolic alterations in the brains of DNP rats to better understand its pathogenesis and identify potential drug targets. In the present study, we identified several DE metabolites in the brains in the DNP group at 4, 8, and

Author contributions

Qi Zhang wrote the manuscript. Qi Zhang, Qingchun Li and Siying Liu accomplished the study together, including acquisition, analysis and interpretation. Lijin Ji, Hangping Zheng and Na Yi participated in the animal study, including rats’ introduction and behavior tests. Xiaoming Zhu and Wanwan Sun analyzed all the data. Shuo Zhang, Xiaoxia Liu, Yiming Li and Qiang Xiong participated in the conception and design, revised manuscripts. Bin Lu made substantial contributions to conception and design

Funding

The present study was supported by grants from the National Natural Science Foundation of China (81770807 to Bin Lu and 81800692 to Lijin Ji), Shanghai Talent Development Fund Program (2018054, to Bin Lu), Shanghai General Hospital Program of Chinese traditional and Western medicine combination (ZY(2018–2020)-FWTX-1002, to Yiming Li), Ministry of Science and Technology Program (2017ZX09304005, to Shuo Zhang), and Shanghai Municipal Commission of Health and Family Planning Clinical Research

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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