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Kynurenic Acid Prevents Cytoskeletal Disorganization Induced by Quinolinic Acid in Mixed Cultures of Rat Striatum

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Abstract

Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan known to modulate a number of mechanisms involved in neural dysfunction. Although its activity in the brain has been widely studied, the effect of KYNA counteracting the actions of quinolinic acid (QUIN) remains unknown. The present study aims at describing the ability of 100 μM KYNA preventing cytoskeletal disruption provoked by QUIN in astrocyte/neuron/microglia mixed culture. KYNA totally preserved cytoskeletal organization, cell morphology, and redox imbalance in mixed cultures exposed to QUIN. However, KYNA partially prevented morphological alteration in isolated primary astrocytes and failed to protect the morphological alterations of neurons caused by QUIN exposure. Moreover, KYNA prevented QUIN-induced microglial activation and upregulation of ionized calcium-binding adapter molecule 1 (Iba-1) and partially preserved tumor necrosis factor-α (TNF-α) level in mixed cultures. TNF-α level was also partially preserved in astrocytes. In addition to the mechanisms dependent on redox imbalance and microglial activation, KYNA prevented downregulation of connexin-43 and the loss of functionality of gap junctions (GJs), preserving cell–cell contact, cytoskeletal organization, and cell morphology in QUIN-treated cells. Furthermore, the toxicity of QUIN targeting the cytoskeleton of mixed cultures was not prevented by the N-methyl-D-aspartate (NMDA) antagonist MK-801. We suggest that KYNA protects the integrity of the cytoskeleton of mixed cultures by complex mechanisms including modulating microglial activation preventing oxidative imbalance and misregulated GJs leading to disrupted cytoskeleton in QUIN-treated cells. This study contributed to elucidate the molecular basis of KYNA protection against QUIN toxicity.

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Acknowledgements

This work was supported by grants of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.

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Authors and Affiliations

  1. Laboratório de Neuroproteção e DoençasMetabólicas, Departamento de Bioquímica, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Paula Pierozan, Helena Biasibetti-Brendler, Felipe Schmitz, Fernanda Ferreira & Angela T S Wyse

  2. Departamento de Bioquímica, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP, Porto Alegre, RS, 90035-003, Brazil

    Paula Pierozan, Regina Pessoa-Pureur & Angela T S Wyse

  3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Helena Biasibetti-Brendler, Felipe Schmitz, Fernanda Ferreira & Angela T S Wyse

  4. Laboratório de Citoesqueleto, Departamento de Bioquímica, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Regina Pessoa-Pureur

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  1. Paula Pierozan
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  2. Helena Biasibetti-Brendler
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Correspondence to Paula Pierozan.

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Highlights

QUIN-elicited cytoskeleton disruption is protected by KYNA.

KYNA protects against QUIN by maintaining redox balance.

Microglial activation caused by QUIN is protected by KYNA effects.

Disturbed cell communication is protected by KYNA through proper cell–cell interaction.

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Pierozan, P., Biasibetti-Brendler, H., Schmitz, F. et al. Kynurenic Acid Prevents Cytoskeletal Disorganization Induced by Quinolinic Acid in Mixed Cultures of Rat Striatum. Mol Neurobiol 55, 5111–5124 (2018). https://doi.org/10.1007/s12035-017-0749-2

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