title: Gap Junction Intercellular Communication Mediates Ammonia-Induced Neurotoxicity.
abstract: Astrocytes are important brain targets of ammonia, a neurotoxin implicated in the development of hepatic encephalopathy. During hyperammonemia, the pivotal role of astrocytes in brain function and homeostasis is impaired. These cells are abundantly interconnected by gap junctions (GJ), which are intercellular channels that allow the exchange of signaling molecules and metabolites. This communication may also increase cellular vulnerability during injuries, while GJ uncoupling could limit the extension of a lesion. Therefore, the current study was performed to investigate whether astrocyte coupling through GJ contributes to ammonia-induced cytotoxicity. We found that carbenoxolone (CBX), an effective GJ blocker, prevented the following effects induced by ammonia in astrocyte primary cultures: (1) decrease in cell viability and membrane integrity; (2) increase in reactive oxygen species production; (3) decrease in GSH intracellular levels; (4) GS activity; (5) pro-inflammatory cytokine release. On the other hand, CBX had no effect on C6 astroglial cells, which are poorly coupled via GJ. To our knowledge, this study provides the first evidence that GJ play a role in ammonia-induced cytotoxicity. Although more studies in vivo are required to confirm our hypothesis, our data suggest that GJ communication between astrocytes may transmit damage signals and excitotoxic components from unhealthy to normal cells, thereby contributing to the propagation of the neurotoxicity of ammonia.
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil. larissabobermin@gmail.com.
authors.forename: Larissa Daniele
authors.initials: LD
authors.lastname: Bobermin
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Bernardo Assein
authors.initials: BA
authors.lastname: Arús
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Marina Concli
authors.initials: MC
authors.lastname: Leite
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.affiliation: Departamento de Bioquímica, 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, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
mesh_terms: D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002229:Carbenoxolone / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D000641:Ammonia; D005978:Glutathione; D002229:Carbenoxolone
keywords: Ammonia; Astrocytes; C6 astroglial cells; Carbenoxolone; Gap junctions