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Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

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Abstract

Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the in vitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The in vivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced in vitro and in vivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2′,7′-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined in vitro and in vivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA in vitro in nerve terminals and in vivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

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Acknowledgments

This work was supported by grants from CNPq, PRONEX II, FAPERGS, PROPESQ/UFRGS, FINEP research grant Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00 and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

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

    Carolina Gonçalves Fernandes, Clarissa Günther Borges, Bianca Seminotti, Alexandre Umpierrez Amaral, Lisiane Aurélio Knebel, Paula Eichler, Anderson Büker de Oliveira, Guilhian Leipnitz & Moacir Wajner

  2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Anderson Büker de Oliveira & Moacir Wajner

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  1. Carolina Gonçalves Fernandes
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Fernandes, C.G., Borges, C.G., Seminotti, B. et al. Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats. Cell Mol Neurobiol 31, 775–785 (2011). https://doi.org/10.1007/s10571-011-9675-4

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