Ornithine and Homocitrulline Impair Mitochondrial Function, Decrease Antioxidant Defenses and Induce Cell Death in Menadione-Stressed Rat Cortical Astrocytes: Potential Mechanisms of Neurological Dysfunction in HHH Syndrome

• Published in: Neurochemical research Vol. 41; no. 9; pp. 2190 - 2198
• Main Authors: Zanatta, Ângela, Rodrigues, Marília Danyelle Nunes, Amaral, Alexandre Umpierrez, Souza, Débora Guerini, Quincozes-Santos, André, Wajner, Moacir
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2016; Springer Nature B.V
• Subjects: Amino Acid Transport Systems, Basic - drug effects; Amino acids; Ammonia; Animals; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Ataxia; Bioaccumulation; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell death; Cell Death - drug effects; Citrulline - analogs & derivatives; Citrulline - pharmacology; Cognitive ability; Cortex; Excretion; Extrapyramidal system; Hyperammonemia; Hyperammonemia - drug therapy; Hyperammonemia - metabolism; Hypotonia; Inflammation; Inflammatory response; Interleukin 6; Iodides; Male; Membrane potential; Menadione; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neurochemistry; Neurological complications; Neurology; Neurosciences; Neurotoxins; NF-κB protein; Original Paper; Ornithine; Ornithine - deficiency; Ornithine - metabolism; Ornithine - pharmacology; Oxidative stress; Pathogenesis; Propidium iodide; Rats, Wistar; Reduction; Spastic paraplegia; Stroke-like episodes; Toxins; Translocase; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Urea Cycle Disorders, Inborn - drug therapy; Urea Cycle Disorders, Inborn - metabolism; Homocitrulline; Oxidative stress; HHH syndrome; Ornithine; Mitochondrial function; Astrocytes
• DOI: 10.1007/s11064-016-1933-x
• ISSN: 0364-3190

Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome is caused by deficiency of ornithine translocase leading to predominant tissue accumulation and high urinary excretion of ornithine (Orn), homocitrulline (Hcit) and ammonia. Although affected patients commonly present neurological dysfunction manifested by cognitive deficit, spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia and ataxia, its pathogenesis is still poorly known. Although astrocytes are necessary for neuronal protection. Therefore, in the present study we investigated the effects of Orn and Hcit on cell viability (propidium iodide incorporation), mitochondrial function (thiazolyl blue tetrazolium bromide—MTT—reduction and mitochondrial membrane potential—ΔΨ m ), antioxidant defenses (GSH) and pro-inflammatory response (NFkB, IL-1β, IL-6 and TNF-α) in unstimulated and menadione-stressed cortical astrocytes that were previously shown to be susceptible to damage by neurotoxins. We first observed that Orn decreased MTT reduction, whereas both amino acids decreased GSH levels, without altering cell viability and the pro-inflammatory factors in unstimulated astrocytes. Furthermore, Orn and Hcit decreased cell viability and ΔΨ m in menadione-treated astrocytes. The present data indicate that the major compounds accumulating in HHH syndrome impair mitochondrial function and reduce cell viability and the antioxidant defenses in cultured astrocytes especially when stressed by menadione. It is presumed that these mechanisms may be involved in the neuropathology of this disease.