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.
PLoS One. 2018 Sep 10;13(9):e0203707. doi: 10.1371/journal.pone.0203707. eCollection 2018.
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.
高血氨症是尿素循环障碍的常见生化特征，会激活神经毒性途径。如果不治疗，受影响的个体有发生不可逆脑损伤和死亡的高风险。在这里，我们表明急性高血氨症强烈增强了依赖转氨作用的渗透调节谷氨酸和兴奋性谷氨酸的形成，从而通过协同过度激活 NMDA 受体和由 2-氧戊二酸耗竭引起的生物能损伤，诱导氨营养型斑马鱼幼虫的神经毒性和死亡。有趣的是，5-氟甲基鸟氨酸对鸟氨酸氨基转移酶（OAT）的特异性和不可逆抑制可使斑马鱼免受致死浓度的乙酸铵的影响，并纠正高血氨症引起的生化改变。因此，OAT 抑制是预防急性高血氨症引起的神经毒性和死亡率的一种有前途且有效的治疗方法。
