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Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure

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Abstract

Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. Clinically, the disease is characterized by progressive neurological deterioration and renal failure, whose pathophysiology is still undefined. In the present study we investigated the effect of acute MMA administration on some important parameters of brain neurotransmission in cerebral cortex of rats, namely Na+, K+-ATPase, ouabain-insensitive ATPases and acetylcholinesterase activities, in the presence or absence of kidney injury induced by gentamicin administration. Initially, thirty-day old Wistar rats received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 μmol/g) or saline, with an 11 h interval between each injection. One hour after the last injection the animals were killed and the cerebral cortex isolated. MMA administration by itself was not able to modify Na+, K+-ATPase, ATPases ouabain-insensitive or acetylcholinesterase activities in cerebral cortex of young rats. In rats receiving gentamicin simultaneously with MMA, it was observed an increase in the activity of acetylcholinesterase activity in cerebral cortex, without any alteration in the activity of the other studied enzymes. Therefore, it may be speculated that cholinergic imbalance may play a role in the pathogenesis of the brain damage. Furthermore, the pathophysiology of tissue damage cannot be exclusively attributed to MMA toxicity, and control of kidney function should be considered as a priority in the management of these patients, specifically during episodes of metabolic decompensation when MMA levels are higher.

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Acknowledgments

This work was supported by grants from CNPq, FAPESC and PROPEX/UNESC.

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Authors and Affiliations

  1. Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    André C. Affonso, Daniele G. Machado, Fernanda Malgarin, Patrícia F. Schuck & Gustavo C. Ferreira

  2. Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Daiane B. Fraga, Fernando Ghedim & Alexandra Zugno

  3. Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Emílio L. Streck

  4. Laboratório de Erros Inatos do Metabolismo, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Avenida Universitária, 1105, Bloco S, Sala 21, 88806-000, Criciúma, SC, Brazil

    Gustavo C. Ferreira

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  1. André C. Affonso
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  2. Daniele G. Machado
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Affonso, A.C., Machado, D.G., Malgarin, F. et al. Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure. Metab Brain Dis 28, 493–500 (2013). https://doi.org/10.1007/s11011-013-9396-0

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