Temporal Dynamics of Glyoxalase 1 in Secondary Neuronal Injury

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.

Glutathione-Dependent Detoxification Processes in Astrocytes

“…Both glyoxalase 1 and glyoxalase 2 are strongly expressed in cultured astrocytes and the specific activity determined for this enzyme is higher in astrocytes than in cultured neurons [129]. Strong immunoreactivity for glyoxalase 1 was also found for astrocytes in mouse and rat brain [129,130]. Cultured astrocytes convert exogenously applied methylglyoxal more efficiently to D-lactate than neurons [129].…”

The temporal and spatial dynamics of glyoxalase I following excitoxicity and brain ischaemia

“…We detected the Glo1 monomer at 23 kDa and the Glo1 dimer at 46 kDa in OHSCs [15]. In untreated OHSCs, no significant changes in Glo1 could be determined over the period of investigation.…”

“…All of the aforementioned diseases are chronic and only a few reports of Glo1 and/or MG in acute brain pathologies are available [15,16]. The role of Glo1 and MG in these events is still not completely elucidated.…”

“…Since the temporal and spatial dynamics of Glo1 in excitotoxicity were not investigated previously, we analysed in our very recent study changes in Glo1 using the in vitro model of OHSCs (organotypic hippocampal slice cultures) lesioned with NMDA [15]. This model is well accepted for examining pharmacological and biochemical effects as well as for morphological changes in excitotoxicity [32,33].…”

AGEs and neurodegeneration: the Nrf2/glyoxalase-1 interaction

“…The functional implications of the Glo-1 dimerization and intracellular redistribution, elsewhere described [8], would need to be further investigated to fully understand the mechanisms of regulation of Glo-1 activity and expression. Anyway, it could be postulated that the accumulation of Glo-1 protein content in brain of high fructose mice was due to post-translational modifications that stabilize Glo-1 dimers preventing their degradation, independently of both its enzymatic activity, which was actually reduced, and possibly reduced mRNA expression, that however was not evaluated in our study [1].…”