Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons.
The hippocampus is known to play a crucial role in learning and memory. Recent data from literature show that cognitive problems, common to aged or diabetic patients, may be related to accumulation of toxic alpha-oxoaldehydes such as methylglyoxal. Thus, it is possible that methylglyoxal could be, at least in part, responsible for the impairment of cognitive functions, and the knowledge of the mechanisms through which this compound elicits neuronal toxicity could be useful for the development of possible therapeutic strategies. We previously reported a high susceptibility of hippocampal neurons to methylglyoxal, through an oxidation-dependent mechanism. In the present study, we extend our investigation on the molecular mechanisms which underlie methylglyoxal toxicity, focusing on possible effects on expression and activity of glyoxalases, its main detoxifying enzymes, and glutathione peroxidase, as well as on the levels of reduced glutathione. We also investigate methylglyoxal-induced modulation of brain derived neurotrophic factor and proinflammatory cytokines. Our results show that methylglyoxal causes a dramatic depletion of reduced glutathione and a significant inhibition of both glyoxalase and glutathione peroxidase activities. Furthermore, methylglyoxal treatment seems to affect the expression of inflammatory cytokines and survival factors. In conclusion, our findings suggest that methylglyoxal-induced neurotoxicity occurs through the impairment of detoxification pathway and depletion of reduced glutathione. This, in turn, triggers widespread apoptotic cell death, occurring through the convergence of both mitochondrial and Fas-receptor pathways.
Di Loreto
Silvia
S
Institute for Organ Transplantation and Immunocytology (ITOI), CNR, P. le Collemaggio, 67100 L'Aquila, Italy. s.diloreto@itoi.cnr.it
Zimmitti
Vincenzo
V
Sebastiani
Pierluigi
P
Cervelli
Carla
C
Falone
Stefano
S
Amicarelli
Fernanda
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008658:Inactivation, Metabolic; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011765:Pyruvaldehyde / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
D019208:Brain-Derived Neurotrophic Factor; D005978:Glutathione; D005979:Glutathione Peroxidase; D007791:Lactoylglutathione Lyase; D011765:Pyruvaldehyde; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase