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Treatment with Blackberry Extract and Metformin in Sporadic Alzheimer’s Disease Model: Impact on Memory, Inflammation, Redox Status, Phosphorylated Tau Protein and Insulin Signaling

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Abstract

Natural products offer promising potential for the development of new therapies for Alzheimer's disease (AD). Blackberry fruits are rich in phytochemical compounds capable of modulating pathways involved in neuroprotection. Additionally, drug repurposing and repositioning could also accelerate the development of news treatments for AD. In light of the reduced brain glucose metabolism in AD, an alternative approach has been the use of the drug metformin. Thus, the aim of this study was to evaluate the effect of treatment with blackberry extract in a model of AD induced by streptozotocin (STZ) and compare it with metformin treatment. Male rats were divided into groups: I - Control; II - STZ; III - STZ + blackberry extract (100 mg/kg); IV - STZ + blackberry extract (200 mg/kg) and V - STZ + metformin (150 mg/kg). The animals received intracerebroventricular injection of STZ or buffer. Seven days after the surgical procedure, the animals were treated orally with blackberry extract or metformin for 21 days. Blackberry extract and metformin prevented the memory impairment induced by STZ. In animals of group II, an increase in acetylcholinesterase activity, phosphorylated tau protein, IL-6, oxidative damage, and gene expression of GSK-3β and Nrf2 was observed in the hippocampus. STZ induced a decrease in IL-10 levels and down-regulated the gene expression of Akt1, IRS-1 and FOXO3a. Blackberry extract and metformin prevented the alterations in acetylcholinesterase activity, IL-6, GSK3β, Nrf2, and oxidative damage. In conclusion, blackberry extract exhibits multi-target actions in a model of AD, suggesting new therapeutic potentials for this neurodegenerative disease.

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Acknowledgements

The authors would like to acknowledge the Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA - Clima Temperado) in Pelotas, RS, Brazil, for providing blackberry fruits.

Funding

This research was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS). This study was financed, in part, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior- Brasil (CAPES)—Finance code 001. R.M.S is a recipient of the CNPq fellowship (310472/2021–0).

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Authors and Affiliations

  1. Programa de Pós‑Graduação em Bioquímica e Bioprospecção, Universidade Federal de Pelotas, Campus Universitário Capão do Leão S/N, Pelotas, RS, CEP 96010‑900, Brazil

    Julia Eisenhardt de Mello, Alessandra dos Santos, Karina Luduvico, Mayara Sandrielly Soares de Aguiar, Vinicius Farias Campos, Augusto Schneider, Francieli Moro Stefanello & Roselia Maria Spanevello

  2. Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, CEP 90050-170, Brazil

    Fernanda Cardoso Teixeira

  3. Programa de Pós-Graduação em Biotecnologia, Universidade Federal de Pelotas, Campus Universitário Capão do Leão, S/N, Pelotas, RS, CEP 96010‑900, Brazil

    William Borges Domingues & Vinicius Farias Campos

  4. Programa de Pós-Graduação em Nutrição e Alimentos, Universidade Federal de Pelotas, Campus Porto, Rua Gomes Carneiro 1, Pelotas, RS, CEP 96010‑610, Brazil

    Augusto Schneider

  5. Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Universidade Federal de Pelotas, Campus Universitário Capão Do Leão S/N, Pelotas, RS, CEP 96010‑900, Brazil

    Rejane Giacomelli Tavares

  6. Centro de Ciências Químicas, Farmacêuticas e de Alimentos/Bioquímica, Laboratório de Neuroquímica, Inflamação e Câncer, Prédio 29, Universidade Federal de Pelotas, Campus Capão do Leão, S/N, CEP 9601090, Caixa Postal 354, Pelotas, RS, Brazil

    Roselia Maria Spanevello

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Contributions

All authors contributed to the study conception and design. Material preparations, data collection and analysis were performed by J.E.M.; F.C.T.; A.S.; K.L.; M.S.S.A.; W.B.; V.C.F.; R.T.; A.S. The first draft of the manuscript was written by J.E.M and R.M.S. Review, editing and funding acquisition was performed by F.M.S. and R.M.S. All authors have read and approved the final manuscript.

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Correspondence to Roselia Maria Spanevello.

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The authors have no relevant financial or non-financial interests to disclose.

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All animal experiments were carried out in accordance with the National Institutes of Health Guidelines for Care and Use of Laboratory Animals and approved by the Ethics Committee on the Use of Animals of the Federal University of Pelotas (protocol number: protocol number: 42067–2019). All animals received care in compliance with the principles of laboratory animal standards.

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de Mello, J.E., Teixeira, F.C., dos Santos, A. et al. Treatment with Blackberry Extract and Metformin in Sporadic Alzheimer’s Disease Model: Impact on Memory, Inflammation, Redox Status, Phosphorylated Tau Protein and Insulin Signaling. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04062-2

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