Quinolinic acid neurotoxicity: Differential roles of astrocytes and microglia via FGF-2-mediated signaling in redox-linked cytoskeletal changes.
QUIN is a glutamate agonist playing a role in the misregulation of the cytoskeleton, which is associated with neurodegeneration in rats. In this study, we focused on microglial activation, FGF2/Erk signaling, gap junctions (GJs), inflammatory parameters and redox imbalance acting on cytoskeletal dynamics of the in QUIN-treated neural cells of rat striatum. FGF-2/Erk signaling was not altered in QUIN-treated primary astrocytes or neurons, however cytoskeleton was disrupted. In co-cultured astrocytes and neurons, QUIN-activated FGF2/Erk signaling prevented the cytoskeleton from remodeling. In mixed cultures (astrocyte, neuron, microglia), QUIN-induced FGF-2 increased level failed to activate Erk and promoted cytoskeletal destabilization. The effects of QUIN in mixed cultures involved redox imbalance upstream of Erk activation. Decreased connexin 43 (Cx43) immunocontent and functional GJs, was also coincident with disruption of the cytoskeleton in primary astrocytes and mixed cultures. We postulate that in interacting astrocytes and neurons the cytoskeleton is preserved against the insult of QUIN by activation of FGF-2/Erk signaling and proper cell-cell interaction through GJs. In mixed cultures, the FGF-2/Erk signaling is blocked by the redox imbalance associated with microglial activation and disturbed cell communication, disrupting the cytoskeleton. Thus, QUIN signal activates differential mechanisms that could stabilize or destabilize the cytoskeleton of striatal astrocytes and neurons in culture, and glial cells play a pivotal role in these responses preserving or disrupting a combination of signaling pathways and cell-cell interactions. Taken together, our findings shed light into the complex role of the active interaction of astrocytes, neurons and microglia in the neurotoxicity of QUIN.
Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Paula
P
Pierozan
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Helena
H
Biasibetti
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Felipe
F
Schmitz
Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Helena
H
Ávila
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mariana M
MM
Parisi
Laboratório de Biologia Molecular, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Florencia
F
Barbe-Tuana
Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Angela T S
AT
Wyse
Laboratório do Citoesqueleto, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: rpureur@ufrgs.br.
Regina
R
Pessoa-Pureur
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D018920:Coculture Techniques; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011247:Pregnancy; D061251:Primary Cell Culture; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D018031:Connexin 43; D018690:Excitatory Amino Acid Agonists; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D017378:Quinolinic Acid
Cell signaling; Cytoskeleton; FGF-2; Gap junction; Glial cell; Quinolinic acid