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Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy

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Abstract

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light–Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

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Data Availability

The datasets analyzed during the study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to Sharing English for the language review of this study.

Funding

This study was funded in part by the ‘Fundação de Amparo à Ciência e Tecnologia de Pernambuco’ (FACEPE, #0989–4.05/22 and #1471–4.05/22) – Brazil, ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico’ (CNPq) (#402426/2021–5 and #131234/2022–6) – Brazil, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES)—(Finance Code 001 and 1238/2022/88881.707895/2022–01) and Instituto Mexicano del Seguro Social (Grant: FIS/IMSS/PROT/19/109).

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Authors and Affiliations

  1. Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil

    Caio Matheus Santos da Silva Calado, Raul Manhães-de-Castro, Sabrina da Conceição Pereira, Vanessa da Silva Souza, Leticia Nicoly Ferreira Barbosa & Ana Elisa Toscano

  2. Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil

    Caio Matheus Santos da Silva Calado, Raul Manhães-de-Castro, Sabrina da Conceição Pereira, Vanessa da Silva Souza, Osmar Henrique dos Santos Junior, Claudia Jacques Lagranha, Omar Guzmán-Quevedo & Ana Elisa Toscano

  3. Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil

    Raul Manhães-de-Castro & Ana Elisa Toscano

  4. Graduate Program in Biochemistry and Physiology, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Claudia Jacques Lagranha

  5. Laboratory of Experimental Neuronutrition and Food Engineering, Tecnológico Nacional de México (TECNM), Instituto Tecnológico Superior de Tacámbaro, 61651, Tacámbaro, Michoacán, Mexico

    Pedro Alberto Romero Juárez & Omar Guzmán-Quevedo

  6. Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, 58330, Morelia, Michoacán, Mexico

    Pedro Alberto Romero Juárez, Luz Torner & Omar Guzmán-Quevedo

  7. Nursing Unit, Vitória Academic Center, Federal University of Pernambuco, Rua Do Alto Do Reservatório S/N, Bela Vista, Vitória de Santo Antão, Pernambuco, 55608-680, Brazil

    Ana Elisa Toscano

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  1. Caio Matheus Santos da Silva Calado
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Contributions

All authors contributed to the study conception and design. C.M.S.S.C: conceptualization, data collection, analysis of result and decided on the manuscript’s structure. R.M.C: intellectual supervision and analysis of results. S.C.P, V.S.S, and L.N.F.B: data collection, results analysis, and writing. O.H.S.J and C.J.L: conducting the gene expression experiments and analysis of results. P.A.R.J, O.G.Q, and L.T: conducting the immunohistochemistry procedure and intellectual supervision. A.E.T: supervision, conceptualization, formal analysis, and decided on the manuscript’s structure.

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Correspondence to Ana Elisa Toscano.

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The present study was conducted in accordance with the recommendations of the National Council for Animal Control and Experimentation (CONCEA-Brazil) and was not initiated until approval had been obtained from the Ethics Committee on Animal Use (process number CEUA- 0082/2022) of the Federal University of Pernambuco (UFPE). All animal experiments were conducted in accordance with the “National Institute of Health Guide for Care and Use of Laboratory Animals” [124].

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Calado, C.M.S.d., Manhães-de-Castro, R., da Conceição Pereira, S. et al. Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy. Mol Neurobiol 61, 3619–3640 (2024). https://doi.org/10.1007/s12035-023-03772-3

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