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Ammonia-Induced Glial-Inflammaging

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Abstract

Astrocytes are functionally diverse glial cells that maintain blood-brain barrier (BBB) integrity, provide metabolic and trophic support, and react to pathogens or harmful stimuli through inflammatory response. Impairment of astrocyte functions has been implicated in hepatic encephalopathy (HE), a neurological complication associated with hyperammonemia. Although hyperammonemia is more common in adults, ammonia gliotoxicity has been mainly studied in cultured astrocytes derived from neonate animals. However, these cells can sense and respond to stimuli in different ways from astrocytes obtained from adult animals. Thus, the aim of this study was to investigate the direct effects of ammonia on astrocyte cultures obtained from adult rats compared with those obtained from neonate rats. Our main findings pointed that ammonia increased the gene expression of proteins associated with BBB permeability, in addition to cause an inflammatory response and decrease the release of trophic factors, which were dependent on p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor κB (NFκB) pathways and aquaporin 4, in both neonatal and mature astrocytes. Considering the age, mature astrocytes presented an overall increase of the expression of inflammatory signaling components and a decrease of the expression of cytoprotective pathways, compared with neonatal astrocytes. Importantly, ammonia exposure in mature astrocytes potentiated the expression of the senescence marker p21, inflammatory response, activation of p38 MAPK/NFκB pathways, and the decrease of cytoprotective pathways. In this regard, ammonia can trigger and/or accelerate the inflammaging of mature astrocytes, a phenomenon characterized by an age-related chronic and low-grade inflammation, which may be implicated in HE neurological symptoms.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Universidade Federal do Rio Grande do Sul, and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN/CNPq).

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  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 – Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil

    Larissa Daniele Bobermin, Carlos-Alberto Gonçalves & André Quincozes-Santos

  2. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Ricardo Haack Amaral Roppa, Carlos-Alberto Gonçalves & André Quincozes-Santos

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  1. Larissa Daniele Bobermin
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  3. Carlos-Alberto Gonçalves
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Correspondence to Larissa Daniele Bobermin.

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All animal experiments were performed in accordance with the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals and Brazilian Society for Neuroscience and Behavior recommendations for animal care. The experimental protocols were approved by the Federal University of Rio Grande do Sul Animal Care and Use Committee (process number 21215).

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Bobermin, L.D., Roppa, R.H.A., Gonçalves, CA. et al. Ammonia-Induced Glial-Inflammaging. Mol Neurobiol 57, 3552–3567 (2020). https://doi.org/10.1007/s12035-020-01985-4

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