title: Methylglyoxal-induced neuroinflammatory response in in vitro astrocytic cultures and hippocampus of experimental animals.
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.
authors.affiliation: Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: John M T
authors.initials: JM
authors.lastname: Chu
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Dicky K M
authors.initials: DK
authors.lastname: Lee
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Daniella P K
authors.initials: DP
authors.lastname: Wong
authors.affiliation: Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. gordon@hku.hk.|Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. gordon@hku.hk.
authors.forename: Gordon T C
authors.initials: GT
authors.lastname: Wong
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. kkmyue@hkbu.edu.hk.
authors.forename: Kevin K M
authors.initials: KK
authors.lastname: Yue
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011765:Pyruvaldehyde / Q000633:toxicity*
chemical_list: D018836:Inflammation Mediators; D011765:Pyruvaldehyde
keywords: Astrocytes; Diabetes; JNK; Methylglyoxal; Neuroinflammation