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.

Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication

“…Elevated MG seems to increase the expression of astrocyte markers (glial fibrillary acidic protein – GFAP and S100B) and cytokines in astrocyte culture and in vivo , leading to astrogliosis and neuroinflammation (Chu et al, 2016). However, cognitive impairment has also been reported without changes in classical parameters of astrogliosis (Hansen et al, 2016b).…”

Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness

“…Increased dicarbonyl stress may affect many organs [13]. Experimental data have shown that this mechanism impairs the renal, cardiovascular, and central nervous system function, at least partially independent of hyperglycaemia [19,20,21]. An in vivo model in non-diabetic mice showed that the knockout of glyoxalase-1, modifies glomerular proteins and oxidative stress in a way that leads to an impaired renal function [19].…”

“…In addition, methylglyoxal increases inflammation, leading to endothelial cell loss that contributes to diabetic cardiomyopathy [22]. The intraperitoneal infusion of methylglyoxal in C57BL/6 mice showed a neuroinflammatory response in astrocytes and the hippocampus, suggesting a methylglyoxal-induced impairment of the central nervous system function [21]. Whether dicarbonyl stress contributes to hepatic or respiratory failure, requires further investigation.…”

“…Dicarbonyl stress has been shown to impair renal function [19], cardiovascular function [20,22], and central nervous system function [21]. Whether it contributes to hepatic or respiratory function, requires further investigation.…”

Systemic inflammation down-regulates glyoxalase-1 expression: an experimental study in healthy males

“…Hypoxia leads to cellular adaptation to low oxygen by activation of hypoxiainducible factors (HIFs) and activation of anaerobic glycolysis, which also may drive dicarbonyl production (11). The produced dicarbonyls damage intracellular and extracellular proteins mainly due to arginine modifications and the formation of methylglyoxal derived hydroimidazolone-1 (MG-H1), leading to cell and tissue dysfunction (12), which has been shown to impair organ function (13)(14)(15)(16).…”