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Methylglyoxal-induced neuroinflammatory response in in vitro astrocytic cultures and hippocampus of experimental animals

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Abstract

Diabetes mellitus is characterized by chronic hyperglycemia and its diverse complications. Hyperglycemia is associated with inflammatory responses in different organs and diabetic patients have a higher risk of developing neurodegenerative disorders. Methylglyoxal is a reactive advanced glycation end product precursor that accumulates in diabetic patients. It induces various stress responses in the central nervous system and causes neuronal dysfunction. Astrocytes are actively involved in maintaining neuronal homeostasis and possibly play a role in protecting the brain against neurodegeneration. However it is not clear whether methylglyoxal exerts any adverse effects towards these astrocytes. In the present study we investigated the effects of methylglyoxal in astrocytic cultures and hippocampi of experimental animals. The cells from the astrocytic line DITNC1 were treated with methylglyoxal for 1 to 24 h. For the in vivo model, 3 months old C57BL/6 mice were treated with methylglyoxal solution for 6 weeks by intraperitoneal injection. Following the treatment, both astrocytes and hippocampi were harvested for MTT assay, Western blot and real time PCR analyses. We found that methylglyoxal induced astrogliosis in DITNC1 astrocytic cultures and C57BL/6 mice. Further, activation of the pro-inflammatory JNK signaling pathway and its downstream effectors c-Jun were observed. Furthermore, increased gene expression of pro-inflammatory cytokines and astrocytic markers were observed from real time PCR analyses. In addition, inhibition of JNK activities resulted in down-regulation of TNF-α gene expression in methylglyoxal treated astrocytes. Our results suggest that methylglyoxal may contribute to the progression of diabetes related neurodegeneration through JNK pathway activation in astrocytes and the subsequent neuroinflammatory responses in the central nervous system.

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Abbreviations

CNS:

Central nervous system

GFAP:

Glial fibrotic acidic protein

IL:

Interleukin

JNK:

c-Jun N-terminal kinases

ROS:

Reactive oxygen species

RT-PCR:

Real time polymerase chain reaction

TGF-β:

Transformation growth factor beta

TNF-α:

Tumor necrosis factor alpha

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Authors and Affiliations

  1. Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    John M. T. Chu

  2. Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    John M. T. Chu & Gordon T. C. Wong

  3. Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    John M. T. Chu & Gordon T. C. Wong

  4. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

    John M. T. Chu, Dicky K. M. Lee, Daniella P. K. Wong & Kevin K. M. Yue

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  1. John M. T. Chu
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  2. Dicky K. M. Lee
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  3. Daniella P. K. Wong
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  4. Gordon T. C. Wong
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  5. Kevin K. M. Yue
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Correspondence to Gordon T. C. Wong or Kevin K. M. Yue.

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The authors have had no financial, personal or other relationships with other people or organizations. This submission contains original work which has not been published previously and it is not under consideration for publication elsewhere.

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John M. T. Chu and Dicky K. M. Lee share equal contributions in this manuscript.

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Chu, J.M.T., Lee, D.K.M., Wong, D.P.K. et al. Methylglyoxal-induced neuroinflammatory response in in vitro astrocytic cultures and hippocampus of experimental animals. Metab Brain Dis 31, 1055–1064 (2016). https://doi.org/10.1007/s11011-016-9849-3

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