Abstract
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.
Highlights
Nitrogen is an essential building block of amino and nucleic acids in all living organisms
To assess whether developing zebrafish embryos are sensitive to NH4+ we exposed them at different stages of embryonic development to varying concentrations of ammonium acetate (NH4Ac) and monitored survival during 36 h after start of exposure
sodium acetate (NaAc) was not toxic to zebrafish larvae at any developmental stage (Fig 1C and 1D) excluding that the acetate compound contributes to the observed toxicity
Summary
Nitrogen is an essential building block of amino and nucleic acids in all living organisms. Protein ingested by food or derived from the body is the major source of excess nitrogen once nitrogen-containing compounds are used to build energy substrates. Deamination of amino acids liberates ammonium (NH4+). If present in increased concentrations, NH4+ is highly toxic to living organisms. While fishes (ammoniotelic organisms) excrete up to 90% of their nitrogenous waste directly into their aqueous environment, reptiles and birds save water by excreting uric acid (uricotelic organisms) [1]. Humans and terrestrial animals (ureotelic organisms) are unable to excrete NH4+ directly or to package large amounts of NH4+ into uric acid and metabolize NH4+ to water-soluble urea, an energy-dependent mechanism requiring three moles of ATP for each mole of urea
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