期刊
NEUROTOXICOLOGY
卷 49, 期 -, 页码 28-35出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.neuro.2015.05.005
关键词
Ammonia; Oxidative stress; Resveratrol; Lipoic acid; Heme oxygenase 1
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
- Financiadora de Estudos e Projetos (FINEP) - IBN Net (Instituto Brasileiro de Neurociencias) [01.06.0842-00]
- Federal University of Rio Grande do Sul (UFRGS)
- Instituto Nacional de Ciencia e Tecnologia para Excitotoxicidade e Neuroprotecao (INCTEN/CNPq)
Ammonia is a metabolite that, at high concentrations, is implicated in neurological disorders, such as hepatic encephalopathy (HE), which is associated with acute or chronic liver failure. Astrocytes are considered the primary target of ammonia toxicity in the central nervous system (CNS) because glutamine synthetase (GS), responsible for ammonia metabolism in CNS, is an astrocytic enzyme. Thus, neuronal dysfunction has been associated as secondary to astrocytic impairment. However, we demonstrated that ammonia can induce direct effects on neuronal cells. The cell viability was decreased by ammonia in SH-SY5Y cells and cerebellar granule neurons. In addition, ammonia induced increased reactive oxygen species (ROS) production and decreased GSH intracellular content, the main antioxidant in CNS. As ammonia neurotoxicity is strongly associated with oxidative stress, we also investigated the potential neuroprotective roles of the antioxidants, resveratrol (RSV) and lipoic acid (LA), against ammonia toxicity in cerebellar granule neurons. RSV and LA were able to prevent the oxidative damage induced by ammonia, maintaining the levels of ROS production and GSH close to basal values. Both antioxidants also decreased ROS production and increased GSH content under basal conditions (in the absence of ammonia). Moreover, we showed that heme oxygenase 1 (HO1), a protein associated with protection against stress conditions, is involved in the beneficial effects of RSV and LA in cerebellar granule neurons. Thus, this study reinforces the neuroprotective effects of RSV and LA. Although more studies in vivo are required, RSV and LA could represent interesting therapeutic strategies for the management of HE. (C) 2015 Elsevier Inc. All rights reserved.
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