Carbonyl stress and NMDA receptor activation contribute to methylglyoxal neurotoxicity.
Methylglyoxal (MG) is a reactive alpha-ketoaldehyde physiologically generated as a by-product of glycolysis. MG that is able to form protein adducts resulting in advanced glycation end products accumulates under conditions associated with neurodegeneration such as impaired glucose metabolism or oxidative stress. In the present study, short-term exposure of human neuroblastoma SH-SY5Y cells to MG was associated with an early depolarization of the plasma membrane, glutamate release, and formation of reactive oxygen species. In addition, long-term exposure (24 h) of SH-SY5Y cells to MG caused a decrease in cell viability, intracellular ATP, and rhodamine 123 (Rh-123) fluorescence. ATP depletion and the decrease in Rh-123 fluorescence were prevented by carbonyl scavengers, the nitric oxide synthase inhibitor L-NAME, and N-methyl-d-aspartate (NMDA) receptor antagonists. Furthermore, the MG-induced glutamate release and the loss in cell viability were prevented by NMDA receptor antagonists. Therefore, MG renders cells more vulnerable to excitotoxicity. In conclusion, carbonyl scavengers as well as NMDA receptor antagonists may represent effective therapeutic tools to reduce the risk of pathophysiological changes associated with carbonyl stress in neurodegenerative diseases.
de Arriba
Susana Garcia
SG
Rudolf-Boehm Institute Pharmacology and Toxicology, University of Leipzig, Germany.
Krügel
Ute
U
Regenthal
Ralf
R
Vissiennon
Zacharie
Z
Verdaguer
Esther
E
Lewerenz
Anne
A
García-Jordá
Elvira
E
Pallas
Mercé
M
Camins
Antoni
A
Münch
Gerald
G
Nieber
Karen
K
Allgaier
Clemens
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D011765:Pyruvaldehyde / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000235:genetics; D020112:Rhodamine 123 / Q000378:metabolism
D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D020112:Rhodamine 123; D018698:Glutamic Acid; D011765:Pyruvaldehyde; D000255:Adenosine Triphosphate