Article

Neurotoxicity Research

, Volume 7, Issue 1, pp 95-101

First online:

The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal

  • Julie WebsterAffiliated withComparative Genomics Centre, James Cook University
  • , Christin UrbanAffiliated withComparative Genomics Centre, James Cook University
  • , Katrin BerbaumAffiliated withComparative Genomics Centre, James Cook University
  • , Claudia LoskeAffiliated withNeuroimmunological Cell Biology Unit, IZKF, Universität Leipzig
  • , Alan AlparAffiliated withDept. of Neuro anatomy, Paul-Flechsig-Institute for Brain Research, University of Leipzig
  • , Ulrich GÄrtnerAffiliated withDept. of Neuro anatomy, Paul-Flechsig-Institute for Brain Research, University of Leipzig
  • , Susana Garcia De ArribaAffiliated withNeuroimmunological Cell Biology Unit, IZKF, Universität Leipzig
  • , Thomas ArendtAffiliated withDept. of Neuro anatomy, Paul-Flechsig-Institute for Brain Research, University of Leipzig
  • , Gerald MÜnchAffiliated withComparative Genomics Centre, James Cook UniversityNeuroimmunological Cell Biology Unit, IZKF, Universität Leipzig Email author 

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Abstract

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 µM 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.

Keywords

Methylglyoxal Carbonyl stress Aminoguanidine Tenilsetam Lipoic acid Neurotoxicity