Abstract
BackgroundEnhanced glycolysis leads to elevated levels of the toxic metabolite methylglyoxal which contributes to loss of protein-function, metabolic imbalance and cell death. Neurons were shown being highly susceptible to methylglyoxal toxicity. Glyoxalase 1 as an ubiquitous enzyme reflects the main detoxifying enzyme of methylglyoxal and underlies changes during aging and neurodegeneration. However, little is known about dynamics of Glyoxalase 1 following neuronal lesions so far.MethodsTo determine a possible involvement of Glyoxalase 1 in acute brain injury, we analysed the temporal dynamics of Glyoxalase 1 distribution and expression by immunohistochemistry and Western Blot analysis. Organotypic hippocampal slice cultures were excitotoxically (N-methyl-D-aspartate, 50 µM for 4 hours) lesioned in vitro (5 minutes to 72 hours). Additionally, permanent middle cerebral artery occlusion was performed (75 minutes to 60 days).ResultsWe found (i) a predominant localisation of Glyoxalase 1 in endothelial cells in non-lesioned brains (ii) a time-dependent up-regulation and re-distribution of Glyoxalase 1 in neurons and astrocytes and (iii) a strong increase in Glyoxalase 1 dimers after neuronal injury (24 hours to 72 hours) when compared to monomers of the protein.ConclusionsThe high dynamics of Glyoxalase 1 expression and distribution following neuronal injury may indicate a novel role of Glyoxalase 1.
Highlights
Methylglyoxal (MG) is a metabolite derived from ketone and threonine metabolisms, but is mainly formed non-enzymatically from triose phosphates degradation along the glycolytic pathway [1,2,3]
Increased MG levels were associated with elevated release of interleukin 1b (IL-1b) and tumour necrosis factor a (TNF-a) in primary neuronal cultures [8,9]
glyoxalase 1 (Glo1) is temporally regulated after excitotoxic lesion The antibody against Glo1 marked two bands with a molecular mass of 23 kDa and 46 kDa (Figure 1A), respectively, representing the monomer and dimer of the enzyme [2]
Summary
Methylglyoxal (MG) is a metabolite derived from ketone and threonine metabolisms, but is mainly formed non-enzymatically from triose phosphates degradation along the glycolytic pathway [1,2,3]. Under anaerobic conditions enhanced glycolysis occurs and an increased amount of MG is formed reaching cytotoxic concentrations [7]. Increased MG levels were associated with elevated release of interleukin 1b (IL-1b) and tumour necrosis factor a (TNF-a) in primary neuronal cultures [8,9]. Neurons show a reduced capacity to adopt their glycolytic rate to anaerobic conditions and are highly susceptible to MG [2,10]. Enhanced glycolysis leads to elevated levels of the toxic metabolite methylglyoxal which contributes to loss of protein-function, metabolic imbalance and cell death. Neurons were shown being highly susceptible to methylglyoxal toxicity. Little is known about dynamics of Glyoxalase 1 following neuronal lesions so far
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