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Ammonia role in glial dysfunction in methylmalonic acidemia

Patricia Gabbi1, Viviane Nogueira1, Fernanda Haupental1

  • 1Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Brazil; Laboratório de Bioquímica do Exercício, Departamento de Métodos e Técnicas Desportivas, Centro de Educação Física e Desportos, UFSM, Brazil; Departamento de Neuropsiquiatria, Centro de Ciências da Saúde, UFSM, Brazil.

Toxicology Letters
|July 17, 2018
PubMed

Insights

Neonatal exposure to methylmalonic acid (MMA) and ammonia (NH4Cl) impairs working memory in mice. This damage is linked to increased inflammation and glial cell activation in the developing brain.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Toxicology

Background:

  • Hyperammonemia is common in methylmalonic acidemia, but its role in MMA-induced neurotoxicity is unclear.
  • Neonatal brain damage may lead to long-term neurodevelopmental disorders, including memory deficits.

Purpose of the Study:

  • To investigate if acute neonatal exposure to MMA and ammonia causes neurodevelopmental deficits.
  • To determine the impact of MMA and ammonia on brain development and function.

Main Methods:

  • Mice received a single intracerebroventricular dose of MMA and/or NH4Cl shortly after birth.
  • Behavioral tests (maze tests) were conducted at 21 and 40 days old.
  • Levels of oxidative stress markers (DCF) and inflammatory cytokines (TNF-α, IL-1β) were measured in brain tissues.

Main Results:

  • MMA and NH4Cl administration resulted in working memory deficits but not reference memory deficits.
  • Increased levels of DCF, TNF-α, and IL-1β were observed in the cortex, hippocampus, and striatum.
  • Glial proliferation was elevated in all studied brain structures.

Conclusions:

  • Acute neonatal exposure to MMA and ammonia can disrupt brain development, leading to memory deficits.
  • Increased cytokine levels suggest glial activation plays a role in MMA and ammonia-induced neurotoxicity.
  • Further research is needed to confirm the speculative link between glial activation and behavioral alterations.
Keywords:
Cerebral cortexGlial proliferationHippocampusInflammatoryMemoryMethylmalonatestriatum

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