A zebrafish model of hyperammonemia

Abstract

Hyperammonemia is the principal consequence of urea cycle defects and liver failure, and the exposure of the brain to elevated ammonia concentrations leads to a wide range of neurocognitive deficits, intellectual disabilities, coma and death. Current treatments focus almost exclusively on either reducing ammonia levels through the activation of alternative pathways for ammonia disposal or on liver transplantation. Ammonia is toxic to most fish and its pathophysiology appears to be similar to that in mammals. Since hyperammonemia can be induced in fish simply by immersing them in water with elevated concentration of ammonia, we sought to develop a zebrafish (Danio rerio) model of hyperammonemia. When exposed to 3 mM ammonium acetate (NH4Ac), 50% of 4-day old (dpf) fish died within 3 hours and 4 mM NH4Ac was 100% lethal. We used 4 dpf zebrafish exposed to 4 mM NH4Ac to test whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) and/or NMDA receptor antagonists MK-801, memantine and ketamine, which are known to protect the mammalian brain from hyperammonemia, prolong survival of hyperammonemic fish. MSO, MK-801, memantine and ketamine all prolonged the lives of the ammonia-treated fish. Treatment with the combination of MSO and an NMDA receptor antagonist was more effective than either drug alone. These results suggest that zebrafish can be used to screen for ammonia-neuroprotective agents. If successful, drugs that are discovered in this screen could complement current treatment approaches to improve the outcome of patients with hyperammonemia.

Mindbomb 2 is dispensable for embryonic development and Notch signalling in zebrafish

“…Hyperammonaemia leads to elevated extracellular glutamate concentrations, which hyperstimulates NMDAR ( Kosenko et al, 2003 ). Several NMDAR antagonists prevent hyperammonaemia-induced death in zebrafish ( Feldman et al, 2014 ). As reported previously, we observed that ammonium acetate (NH 4 Ac) treatment significantly decreased survival compared with the control sodium acetate (NaAc) treatment ( Fig.…”

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

“…Since zebrafish larvae lack a functional urea cycle after hatching, they endogenously mimic the metabolic situation of patients with UCDs who suffer from the functional consequences of defective ureagenesis. Moreover, increasing the concentration of NH 4 + ions in the water by addition of NH 4 Ac is a convenient way to induce acute hyperammonemia in zebrafish larvae [ 38 ]. This approach enabled us to investigate the effects of toxic ammonium concentrations on biochemical and gene regulation as well as survival in a per se urea cycle-deficient organism including the efficacy of different therapeutic interventions.…”

In Vitro and In Vivo Biocompatibility of Novel Zwitterionic Poly(Beta Amino)Ester Hydrogels Based on Diacrylate and Glycine for Site‐Specific Controlled Drug Release

“…This effect could be attributed to the glycine based degradation products found in the material extracts of all the hydrogel samples. Nitrogen containing PBAE hydrogel and its degradation products are metabolized in the zebrafish liver into ammonia, a nitrogen waste product, which can cause local damage to the zebrafish . Since sample H3 has the least amount of glycine residues, it did not show liver damage, even at the highest concentration of extracts (200 µg mL −1 ).…”