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Protective effects of rosmarinic acid against autistic-like behaviors in a mouse model of maternal separation stress: behavioral and molecular amendments

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with worldwide increasing incidence. Maternal separation (MS) stress at the beginning of life with its own neuroendocrine changes can provide the basis for development of ASD. Rosmarinic acid (RA) is a phenolic compound with a protective effect in neurodegenerative diseases. The aim of this study was to determine the effect of RA on autistic-like behaviors in maternally separated mice focusing on its possible effects on neuroimmune response and nitrite levels in the hippocampus. In this study, 40 mice were randomly divided into five groups of control (received normal saline (1 ml/kg)) and MS that were treated with normal saline (1 ml/kg) or doses of 1, 2, and 4 mg/kg RA, respectively, for 14 days. Three-chamber sociability, shuttle box, and marble burying tests were used to investigate autistic-like behaviors. Nitrite level and gene expression of inflammatory cytokines including TNF-α, IL-1β, TLR4, and iNOS were assessed in the hippocampus. The results showed that RA significantly increased the social preference and social novelty indexes, as well as attenuated impaired passive avoidance memory and the occurrence of repetitive and obsessive behaviors in the MS mice. RA reduced the nitrite level and gene expression of inflammatory cytokines in the hippocampus. RA, probably via attenuation of the nitrite level as well as of the neuroimmune response in the hippocampus, mitigated autistic-like behaviors in maternally separated mice.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are thankful for Mr. Vahid Reisi-Vanani and Mrs. Maryam Hashemi for their contribution to this study.

Funding

This study was supported by a research grant (3738) from Shahrekord University of Medical Sciences, Shahrekord, Iran.

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Authors and Affiliations

  1. Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Maziar Mahmoudian

  2. Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Zahra Lorigooini, Mohammad Rahimi-Madiseh, Sahreh Shabani & Hossein Amini-Khoei

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  1. Maziar Mahmoudian
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  2. Zahra Lorigooini
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  3. Mohammad Rahimi-Madiseh
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  4. Sahreh Shabani
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Contributions

M.M: investigation, methodology, visualization, and writing original draft. Z.L: methodology and visualization. M.R-M: methodology, writing, reviewing, and editing. S.S: software, visualization, and methodology. H.A-K: conceptualization, supervision, methodology, resources, Writing, review, editing, project administration, and funding acquisition. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Hossein Amini-Khoei.

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All the procedures in this experiment were carried out following the Shahrekord University of Medical Sciences’s rules for the Care and Use of Laboratory Animals (Ethics code: IR.SKUMS.AEC.1400.001) and Guide for the Care and Use of Laboratory Animals (8th edition, National Academies Press). Full efforts were made to limit animal use and improve their welfare.

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Mahmoudian, M., Lorigooini, Z., Rahimi-Madiseh, M. et al. Protective effects of rosmarinic acid against autistic-like behaviors in a mouse model of maternal separation stress: behavioral and molecular amendments. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03143-2

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