Methylglyoxal induces apoptosis through oxidative stress-mediated activation of p38 mitogen-activated protein kinase in rat Schwann cells.
Although recent studies have suggested the potential involvement of apoptotic cell death in the development of diabetic neuropathy, the precise mechanism remains to be elucidated. On the other hand, it is known that the formation of methylglyoxal (MG), a highly reactive dicarbonyl compound, is accelerated under diabetic conditions through several glucose-related metabolisms including the glycation reaction. We found that MG was capable of inducing apoptosis in peripheral nerve-derived Schwann cells (SCs) in a time- and dose-dependent manner, accompanied by a reduction of intracellular glutathione content. Furthermore, MG induced phosphorylation of MKK3/MKK6, an upstream molecule in the p38 MAPK pathway. N-acetyl-L-cysteine, an antioxidant, successfully suppressed the activity of the p38 MAPK signaling pathway along with the inhibition of apoptosis, indicating the involvement of oxidative stress in the MG-induced apoptosis via the p38 MAPK pathway. These results suggest a possible contribution of glucose-derived MG to the development of diabetic neuropathy by injuring the cellular constituent of the peripheral nerve system, such as SCs, in the hyperglycemic milieu.
Fukunaga
Michiru
M
Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Miyata
Satoshi
S
Higo
Satomi
S
Hamada
Yasuhiro
Y
Ueyama
Shigemitsu
S
Kasuga
Masato
M
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D004789:Enzyme Activation; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000975:Antioxidants; D011765:Pyruvaldehyde; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine