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

被引：23

作者：

Zielonka, Matthias ^{[1
,2
]}

Breuer, Maximilian ^{[1
]}

Okun, Juergen Guenther ^{[1
]}

Carl, Matthias ^{[3
,4
]}

Hoffmann, Georg Friedrich ^{[1
]}

Koelker, Stefan ^{[1
]}

机构：

[1] Univ Hosp Heidelberg, Ctr Child & Adolescent Med, Div Pediat Neurol & Metab Med, Heidelberg, Germany

[2] HRCMM, Heidelberg, Germany

[3] Heidelberg Univ, Med Fac Mannheim, Dept Cell & Mol Biol, Mannheim, Germany

[4] Univ Trento, Ctr Integrat Biol CIBIO, Lab Translat Neu rogenet, Trento, Italy

来源：

PLOS ONE | 2018年 / 13卷 / 09期

关键词：

UREA CYCLE DISORDERS; MITOCHONDRIAL PERMEABILITY TRANSITION; ACUTE LIVER-FAILURE; GLUTAMATE TRANSPORTER; NMDA RECEPTORS; AMINO-ACIDS; OXYGEN-METABOLISM; BRAIN-LESIONS; MOUSE MODEL; CELL-DEATH;

D O I：

10.1371/journal.pone.0203707

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：24