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Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease

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Abstract

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2′,7′-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

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Data Availability

All data generated or analyzed during this study are included in this published article and available upon request.

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Funding

This research was supported by the Higher Education Personnel (CAPES), the Brazilian National Council for Scientific and Technological Development (CNPq), the Santa Catarina State Research and Innovation Support Foundation (Fapesc), and the University of Southern Santa Catarina (UNESC).

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Authors and Affiliations

  1. Programa de Pós-graduação em Ciências da Saúde, Laboratório de Doenças Neurometabólicas, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Isabela da Silva Lemos, Carolina Antunes Torres, Carolina Giassi Alano, Rafaela Tezza Matiola, Rejane de Figueiredo Seldenreich, Pauline Souza Effting & Emilio Luiz Streck

  2. Programa de Pós-graduação em Ciências da Saúde, Laboratório de Psiquiatria Translacional, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Alex Paulo Zeferino Padilha & Gislaine Zilli Réus

  3. Programa de Pós-graduação em Ciências da Saúde, Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Ellen De Pieri & Ricardo Andrez Machado-De-Ávila

  4. Programa de Pós-graduação em Ciências Biológicas: Bioquímica, Departamento de 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

    Guilhian Leipnitz

  5. Programa de Pós-graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil

    Guilhian Leipnitz

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  1. Isabela da Silva Lemos
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  2. Carolina Antunes Torres
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  3. Carolina Giassi Alano
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  6. Alex Paulo Zeferino Padilha
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  10. Gislaine Zilli Réus
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  11. Guilhian Leipnitz
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  12. Emilio Luiz Streck
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Contributions

Conception and design of the research: ISL, GL, ELS. Acquisition of data: ISL, HTB, EP, CAT, CGA, RTM, RFS, APP. Analysis and interpretation of the data: ISL, RAMÁ, GZR, EPR, ELS. Obtaining financing: ELS. Writing of the manuscript: ISL. Critical revision of the manuscript for intellectual content: GL, ELS.

Corresponding author

Correspondence to Emilio Luiz Streck.

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Competing interest

The authors declare no competing interests.

Ethical Approval

The experimental procedures were previously approved by the ethics committee of the UNESC (Protocol number 30/2020 and 37/2021) and followed the National Institutes of Health Guide for Care and Use of Laboratory Animals.

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Lemos, I.S., Torres, C.A., Alano, C.G. et al. Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease. Neurochem Res 49, 758–770 (2024). https://doi.org/10.1007/s11064-023-04072-x

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