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Effects of cannabidiol in post-stroke mood disorders in neonatal rats

Pediatric Research (2024)Cite this article

Abstract

Background

Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development.

Methods

Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls.

Results

CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function.

Conclusions

These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO.

Impact

  • MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system.

  • The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function.

  • These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults.

  • Our work confirms the interest of CBD as a possible treatment for neonatal stroke.

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Fig. 1: Assessment of brain damage in rats submitted to MCAO at 7 days of life (P7) and then receiving vehicle (MCAO + VEH) or CBD 5 mg/Kg (MCAO + CBD), and the corresponding healthy controls (SHAM).
Fig. 2: Assessment of mood disorders in rats submitted to MCAO at 7 days of life (P7) and then receiving vehicle (MCAO + VEH) or CBD 5 mg/Kg (MCAO + CBD), and the corresponding healthy controls (SHAM).
Fig. 3: Assessment of dopamine system in rats submitted to MCAO at 7 days of life (P7) and then receiving vehicle (MCAO + VEH) or CBD 5 mg/Kg (MCAO + CBD), and the corresponding healthy controls (SHAM).

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Data availability

The datasets generated during and/or analyzed in this study are available from the corresponding author on reasonable request.

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Acknowledgements

We wish to thank Carlos Vargas and Alysha Hernández for excellent assistance and Jason Willis-Lee for scientific writing assistance This research was funded by the PI19/00927, PID2019-106404RB-I00 and RD21/0012/0023 projects, integrated in the Plan Nacional de R + D + I, AES 2017-2020 and 2021-2023, funded by the “Instituto de Salud Carlos III” (ISCIII) and co-funded by the European Regional Development Fund (ERDF) “A way to make Europe” and Next Generation EU funds (supporting actions from Resilience and Recovery Mechanisms [MRR]), and the Basque Government (IT1512/22).

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Authors and Affiliations

  1. Biomedical Research Foundation, Hospital Clínico San Calos-IdISSC, Madrid, Spain

    María Villa, María Martínez-Vega, Laura Silva, Aarón del Pozo, María de Hoz-Rivera, Angela Romero & José Martínez-Orgado

  2. Department of Pharmacology, University of the Basque Country, UPV/EHU, Bizkaia, Spain

    Itziar Muneta-Arrate, Carolina Muguruza & Luis F. Callado

  3. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Bizkaia, Spain

    Itziar Muneta-Arrate, Carolina Muguruza & Luis F. Callado

  4. Servicio de Neurobiología-Investigación, Hospital Ramón y Cajal, Madrid, Spain

    Ana Gómez-Soria & Maria José Casarejos

  5. Biocruces-Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain

    Luis F. Callado

  6. Department of Neonatology, Hospital Clínico San Calos-IdISSC, Madrid, Spain

    José Martínez-Orgado

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  1. María Villa
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Contributions

Conceptualization, M.V. and J.M-O; methodology, M.V., L.F.C, M.J.C and J.M-O.; experimental model and neurobehavioral studies: M.V., M.M-V, A.H.; histologic and biochemical studies: M.dH-R, A.R., L.S.; HPLC A.G-S., M.J.C; [35S]GTPγS binding assays: I.M-A, C.M., L.F.C; data curation: M.V., M.M-V, A.H, I.M-A, A.G-S., C.M, M.dH-R, A.R., L.S; data analysis: M.V., L.F.C, M.J.C and J.M-O; writing—original draft preparation, J.M-O; writing—review and editing, M.V., L.F.C, M.J.C and J.M-O.; funding acquisition, L.F.C, M.J.C and J.M-O. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to José Martínez-Orgado.

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Villa, M., Martínez-Vega, M., Silva, L. et al. Effects of cannabidiol in post-stroke mood disorders in neonatal rats. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03077-8

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  • DOI: https://doi.org/10.1038/s41390-024-03077-8

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