The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal.
Advanced glycation end products (AGEs) have been identified in age-related intracellular protein deposits of Alzheimer's disease (amyloid plaques and neurofibrillary tangles) and Parkinson disease (Lewy bodies), suggesting that these protein deposits have been exposed to AGE precursors such as the reactive dicarbonyl compound methylglyoxal. In ageing tissue and under diabetic pseudohypoxia, intracellular methylglyoxal levels rise through an impairment of triosephosphate utilization. Furthermore, methylglyoxal detoxification is impaired when reduced glutathione levels are low, conditions, which have all been described in Alzheimer's disease. However, there is less known about the toxicity of methylglyoxal, particularly about therapeutic strategies to scavenge such dicarbonyl compounds and attenuate their toxicity. In our study, extracellularly applied methylglyoxal was shown to be toxic to human neuroblastoma cells in a dose-dependent manner above concentrations of 150 microM with a LD50 of approximately 1.25 mM. Pre-incubation of methylglyoxal with a variety of carbonyl scavengers such as aminoguanidine or tenilsetam and the thiol antioxidant lipoic acid significantly reduced its toxicity. In summary, carbonyl scavengers might offer a promising therapeutic strategy to reduce the neurotoxicity of reactive carbonyl compounds, providing a potential benefit for patients with age-related neurodegenerative diseases.
Webster
Julie
J
Comparative Genomics Centre, James Cook University, Townsville 4811, Australia.
Urban
Christin
C
Berbaum
Katrin
K
Loske
Claudia
C
Alpar
Alan
A
Gärtner
Ulrich
U
de Arriba
Susana Garcia
SG
Arendt
Thomas
T
Münch
Gerald
G
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013876:Thiophenes / Q000494:pharmacology*
D016166:Free Radical Scavengers; D006146:Guanidines; D018696:Neuroprotective Agents; D010879:Piperazines; D013876:Thiophenes; D011765:Pyruvaldehyde; C059511:tenilsetam; C004479:pimagedine