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Effects of the AMPAR Antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload

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Abstract

Iron accumulation has been associated with the pathogenesis of neurodegenerative diseases and memory decline. As previously described by our research group, iron overload in the neonatal period induces persistent memory deficits and increases oxidative stress and apoptotic markers. The neuronal insult caused by iron excess generates an energetic imbalance that can alter glutamate concentrations and thus trigger excitotoxicity. Drugs that block glutamatergic receptor eligibly mitigate neurotoxicity; among them is perampanel (PER), a reversible AMPA receptor (AMPAR) antagonist. In the present study, we sought to investigate the neuroprotective effects of PER in rats subjected to iron overload in the neonatal period. Recognition and aversive memory were evaluated, AMPAR subunit phosphorylation, as well as the relative expression of genes such as GRIA1, GRIA2, DLG4, and CAC, which code proteins involved in AMPAR anchoring. Male rats received vehicle or carbonyl iron (30 mg/kg) from the 12th to the 14th postnatal day and were treated with vehicle or PER (2 mg/kg) for 21 days in adulthood. The excess of iron caused recognition memory deficits and impaired emotional memory, and PER was able to improve the rodents’ memory. Iron increased the phosphorylation of GLUA1 subunit, which was reversed by PER. Furthermore, iron overload increased the expression of the GRIA1 gene and decreased the expression of the DLG4 gene, demonstrating the influence of metal accumulation on the metabolism of AMPAR. These results suggest that iron can interfere with AMPAR functionality, through altered phosphorylation of its subunits, and the expression of genes that code for proteins critically involved in the assembly and anchoring of AMPAR. The blockade of AMPAR with PER is capable of partially reversing the cognitive deficits caused by iron overload.

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Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This work was supported by National Council for Scientific and Technological Development [CNPq; grant numbers 403154/2021–9 and 305656/2019–8 to N.S.]; the National Institute of Science and Technology for Translational Medicine [INCT-TM—grant number 465458/2014–9]; and Rio Grande do Sul State Research Foundation (FAPERGS—grant number 22/2551–0000385-0); N.S. is Research Career Awardee of the CNPq. The funding sources were not involved in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Authors and Affiliations

  1. Laboratory of Memory Dysfunctions, Department of Physiology, Institute for Basic Health Sciences, Federal University of Rio Grande Do Sul, Porto Alegre, Brazil

    José da Silva, Lariza Oliveira de Souza, Maria Paula Arakaki Severo, Sarah Luize Camargo Rodrigues, Patrícia Molz, Patrícia Schonhofen & Nadja Schröder

  2. National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brasilia, Brazil

    Patrícia Schonhofen & Nadja Schröder

  3. Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande Do Sul, Porto Alegre, Brazil

    Alice Laschuk Herlinger

  4. National Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology–INCT BioOncoPed, Porto Alegre, Brazil

    Alice Laschuk Herlinger

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  1. José da Silva
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  2. Lariza Oliveira de Souza
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Contributions

Conceptualization: J da Silva, N Schroder; methodology: J da Silva and N Schroder; formal analysis and investigation: J da Silva, LO de Souza, MPA Severo, SLC Rodrigues, P Molz, P Schonhofen, and AL Herlinger; writing—original draft preparation: J da Silva; writing—review and editing: N Schroder; funding acquisition: N Schroder; resources: MPA Severo, S L C Rodrigues, and P Molz; supervision: N Schroder.

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Correspondence to Nadja Schröder.

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This study was approved by the Institutional Ethics Committee for the Use of Animals of the Federal University of Rio Grande do Sul (CEUA, #35604), and all experimental procedures were performed in accordance with the Brazilian Guidelines for the Care and Use of Animals in Research and Teaching (DBCA, published by CONCEA, MCTI, Brazil).

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da Silva, J., de Souza, L.O., Severo, M.P.A. et al. Effects of the AMPAR Antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04180-x

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