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

Abstract

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.

ApoA-I Nanoparticles as Curcumin Carriers for Cerebral Endothelial Cells: Improved Cytoprotective Effects against Methylglyoxal

“…Methylglyoxal (MGO) is a highly reactive metabolite of glucose metabolism whose levels are increased in type II diabetic patients. It has been shown to accumulate in the brain of mice deficient for glyoxalase 1/vitamin B6 (MGO detoxification system), suggesting that this imbalance is particularly critical for MGO accumulation in the brain [ 17 ]. Studies have shown that the dysfunction of the glyoxalase system is related to several diabetic complications, including macrovascular diseases in humans [ 18 ].…”

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“…These findings suggest that Glo1 deletion alone is insufficient to increase MG levels in the brain, and MG accumulation in the brain occurs only when another MG detoxification is deficit, such as VB6 deficiency. In fact, we could also confirm the accumulation of MG-H1, an MG-derived AGE, in the brains of KO/VB6(−) mice [ 67 ].…”