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Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases

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Abstract

Carbonyl compounds such as methylglyoxal (MGO) seem to play an important role in complications resulting from diabetes mellitus, in aging and neurodegenerative disorders. In this study, we are showing, that MGO is able to suppress cell viability and induce apoptosis in the cerebral cortex and hippocampus of neonatal rats ex-vivo. These effects are partially related with ROS production, evaluated by DCFH-DA assay. Coincubation of MGO and reduced glutathione (GSH) or Trolox (vitamin E) totally prevented ROS production but only partially prevented the MGO-induced decreased cell viability in the two brain structures, as evaluated by the MTT assay. Otherwise, L-NAME, a nitric oxide (NO) inhibitor, partially prevented ROS production in the two structures but partially prevented cytotoxicity in the hippocampus. Pharmacological inhibition of Erk, has totally attenuated MGO-induced ROS production and cytotoxicity, suggesting that MEK/Erk pathway could be upstream of ROS generation and cell survival. Otherwise, p38MAPK and JNK failed to prevent ROS generation but induced decreased cell survival consistent with ROS-independent mechanisms. We can propose that Erk, p38MAPK and JNK are involved in the cytotoxicity induced by MGO through different signaling pathways. While Erk could be an upstream effector of ROS generation, p38MAPK and JNK seem to be associated with ROS-independent cytotoxicity in neonatal rat brain. The cytotoxic damage progressed to apoptotic cell death at MGO concentration higher than those described for adult brain, suggesting that the neonatal brain is resistant to MGO-induced cell death. The consequences of MGO-induced brain damage early in life, remains to be clarified. However, it is feasible that high MGO levels during cortical and hippocampal development could be, at least in part, responsible for the impairment of cognitive functions in adulthood.

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Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Propesq-UFRGS.

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 anexo, 90035-003, Porto Alegre, RS, Brazil

    Luana Heimfarth, Samanta Oliveira Loureiro, Paula Pierozan, Bárbara Ortiz de Lima, Karina Pires Reis, Elisandra Barbosa Torres & Regina Pessoa-Pureur

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  1. Luana Heimfarth
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  2. Samanta Oliveira Loureiro
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  3. Paula Pierozan
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  4. Bárbara Ortiz de Lima
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Correspondence to Regina Pessoa-Pureur.

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Heimfarth, L., Loureiro, S.O., Pierozan, P. et al. Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases. Metab Brain Dis 28, 429–438 (2013). https://doi.org/10.1007/s11011-013-9379-1

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