Glycolaldehyde induces sensory neuron death through activation of the c-Jun N-terminal kinase and p-38 MAP kinase pathways
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Glycolaldehyde (GA) is a highly reactive hydroxyaldehyde and one of the glycolytic metabolites producing advanced glycation endproducts (AGEs), but its toxicity toward neurons and Schwann cells remains unclear. In the present study, we found that GA exhibited more potent toxicity than other AGE precursors (glyceraldehyde, glyoxal, methylglyoxal and 3-deoxyglucosone) against immortalized IFRS1 adult rat Schwann cells and ND7/23 neuroblastoma × neonatal rat dorsal root ganglion (DRG) neuron hybrid cells. GA affected adult rat DRG neurons and ND7/23 cells more severely than GA-derived AGEs, and exhibited concentration- and time-dependent toxicity toward ND7/23 cells (10 < 100 < 250 < 500 µM; 6 h < 24 h). Treatment with 500 µM GA significantly up-regulated the phosphorylation of c-jun N-terminal kinase (JNK) and p-38 mitogen-activated kinase (p-38 MAPK) in ND7/23 cells. Furthermore, GA-induced ND7/23 cell death was significantly inhibited due to co-treatment with 10 µM of the JNK inhibitor SP600125 or the p-38 MAPK inhibitor SB239063. These findings suggest the involvement of JNK and p-38 MAPK-signaling pathways in GA-induced neuronal cell death and that enhanced GA production under diabetic conditions might be involved in the pathogenesis of diabetic neuropathy.
KeywordsDiabetic neuropathy Sensory neurons Schwann cells Viability Glycolytic metabolites Mitogen-activated protein kinase signaling
Advanced glycation endproducts
Dorsal root ganglia
Immortalized adult Fischer rat Schwann cell 1
c-Jun N-terminal kinase
Mitogen-activated protein kinase
Peripheral nervous system
This study was supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (JSPS KAKENHI 16K07048). We would like to thank Prof. Atsufumi Kawabata and Dr. Fumiko Sekiguchi (Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, Japan) for providing us ND7/23 cells, and Prof. Shuji Mori (Department of Pharmacology, School of Pharmacy, Shujitsu University, Okayama, Japan) for helpful suggestions on AGEs’ preparation.
TA designed and conducted the experiments, and wrote the manuscript. ST, MS, NN, HY, KM, DK, KU, and RN conducted the experiments and discussed the results. KS designed the experiments, wrote the manuscript, and supervised the project.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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