Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits.

Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice (KO/VB6 (-) mice), which are susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a CS-SCZ model to analyze MGO-modified protein and the carbonyl stress status in the brain. A comparison between Wild/VB6(+) mice and KO/VB6(-) mice for accumulated carbonyl proteins levels, with several advanced glycation end products (AGEs) in the brain, revealed that carbonyl protein levels with the Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl) ornithine (MG-H1) moiety were significantly increased in the hippocampus, prefrontal cortex, striatum, cerebral cortex, and brainstem regions of the brain in KO/VB6(-) mice. Moreover, two-dimensional electrophoresis and Liquid chromatography-tandem mass spectrometry analysis showed MG-H1-modified arginine residues in mitochondrial creatine kinase, beta-adrenergic receptor kinase 1, and T-complex protein in the hippocampus region of KO/VB6(-) mice, but not in Wild/VB6(+) mice. In particular, MG-H1 modification of mitochondrial creatine kinase was quite notable. These results suggest that further studies focusing on MG-H1-modified and accumulated proteins in the hippocampus may reveal the onset mechanism of CS-SCZ induced by MGO-induced oxidative damages.

Age-related alteration in the distribution of methylglyoxal and its metabolic enzymes in the mouse brain.

Methylglyoxal (MG) is an α-dicarbonyl compound that is naturally produced in vivo through glucose metabolism. In general, MG is metabolized by the glyoxalase 1(GLO1)/GLO2 system and aldose reductase (AR); however, excessive MG can react with proteins and nucleic acids to induce the accumulation of advanced glycation end products (AGEs). Recently, the accumulation of AGEs in the brain has been presumed to be related to neurodegenerative diseases such as Parkinson's and Alzheimer's disease, respectively. Research investigating the role of AGEs in such diseases is ongoing. However, the changes in MG concentration that occur in the brain during healthy ageing remain unclear. Therefore, we performed fractionation of the brains of aged and young mice, measured the MG concentration in each part of the brain, and then examined the distribution. We also investigated the expression levels of GLO1 and AR, the main metabolizing enzymes of MG, in various brain regions, across age groups. We show that MG concentration varies among different regions of the brain, and that MG concentration in aged mice is significantly lower than that in young mice across all regions of the brain, except the brain stem. In addition, although the expression level of the GLO1 protein in the brain did not change with ageing, the expression level of AR was higher in aged than in young mice. Moreover, although a significant positive correlation was observed between GLO1 expression and MG concentration in the brains of young mice, no significant correlations were observed in the brains of aged mice. Meanwhile, the production of protein carbonyls and the accumulation of AGEs were not observed in the brains of aged mice. These results suggest that the accumulation of MG in the brain, along with the carbonyl stress are suppressed and regionally controlled during healthy ageing. This finding is useful as the foundation for further studies to investigate the role and toxicity of MG in various age-related disease conditions.