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Glia-related Acute Effects of Risperidone and Haloperidol in Hippocampal Slices and Astrocyte Cultures from Adult Wistar Rats: A Focus on Inflammatory and Trophic Factor Release

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Abstract

Antipsychotics are drugs commonly prescribed to treat a variety of psychiatric conditions. They are classified as typical and atypical, depending on their affinity for dopaminergic and serotonergic receptors. Although neurons have been assumed to be the major mediators of the antipsychotic pharmacological effects, glia, particularly astrocytes, have emerged as important cellular targets for these drugs. In the present study, we investigated the effects of acute treatments with the antipsychotics risperidone and haloperidol of hippocampal slices and astrocyte cultures, focusing on neuron-glia communication and how antipsychotics act in astrocytes. For this, we obtained hippocampal slices and primary astrocyte cultures from 30-day-old Wistar rats and incubated them with risperidone or haloperidol (1 and 10 μM) for 30 min and 24 h, respectively. We evaluated metabolic and enzymatic activities, the glutathione level, the release of inflammatory and trophic factors, as well as the gene expression of signaling proteins. Haloperidol increased glucose metabolism; however, neither of the tested antipsychotics altered the glutathione content or glutamine synthetase and Na+K+-ATPase activities. Haloperidol induced a pro-inflammatory response and risperidone promoted an anti-inflammatory response, while both antipsychotics seemed to decrease trophic support. Haloperidol and risperidone increased Nrf2 and HO-1 gene expression, but only haloperidol upregulated NFκB and AMPK gene expression. Finally, astrocyte cultures confirmed the predominant effect of the tested antipsychotics on glia and their opposite effects on astrocytes. Therefore, antipsychotics cause functional alterations in the hippocampus. This information is important to drive future research for strategies to attenuate antipsychotics-induced neural dysfunction, focusing on glia.

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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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Acknowledgements

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 (INCTEN/CNPq).

Funding

This research was supported by 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) and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção.

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências, Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil

    Amanda da Silva, Larissa Daniele Bobermin, Camila Leite Santos, Tiago Marcon dos Santos, Marina Seady, Marina Concli Leite, Angela T. S. Wyse, Carlos-Alberto Gonçalves & André Quincozes-Santos

  2. Programa de Pós-Graduação Em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil

    Larissa Daniele Bobermin, Rômulo Rodrigo de Souza Almeida, Carlos-Alberto Gonçalves & André Quincozes-Santos

  3. Departament of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

    Lílian Juliana Lissner

  4. Departamento de 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

    Marina Concli Leite, Angela T. S. Wyse, Carlos-Alberto Gonçalves & André Quincozes-Santos

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  1. Amanda da Silva
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  2. Larissa Daniele Bobermin
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  11. André Quincozes-Santos
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Contributions

AS and AQS conceptualized the study. AS, LDB, CLS, RRSA, LJL, TMS, and MPS performed the experiments. AS, LDB, and AQS performed statistical analysis and written the original draft of the manuscript. MCL, ATSW, CAG, and AQS provided resources and materials/chemicals. All authors revised, edited, and approved the manuscript.

Corresponding author

Correspondence to André Quincozes-Santos.

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The authors declare no competing interests.

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This study protocol was reviewed and approved by the Federal University of Rio Grande do Sul Animal Care and Use Committee (process number 35557).

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da Silva, A., Bobermin, L.D., Santos, C.L. et al. Glia-related Acute Effects of Risperidone and Haloperidol in Hippocampal Slices and Astrocyte Cultures from Adult Wistar Rats: A Focus on Inflammatory and Trophic Factor Release. Neurochem Res 50, 22 (2025). https://doi.org/10.1007/s11064-024-04273-y

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