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PLoS One. 2018 Sep 10;13(9):e0203707. doi: 10.1371/journal.pone.0203707. eCollection 2018.

Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase.

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University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany.
Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany.
Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Mannheim, Germany.
University of Trento, Center for Integrative Biology (CIBIO), Laboratory of Translational Neurogenetics, Trento, Italy.


Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.

Conflict of interest statement

The authors have declared that no competing interests exist.

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