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Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity

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Abstract

Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.

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Acknowledgements

This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Universidade Estadual de Maringá and FAPESP (2017/24304-0), São Paulo, Brazil. The authors thank ADCA – Indústria e Comércio de Material Cirúrgico for kindly donating the aneurysm clips and Marco Alberto Trombelli for his technical support.

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Universidade Estadual de Maringá, Paraná, Brazil and FAPESP (2017/24304–0), São Paulo, Brazil.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, Maringá, Paraná, 5790, 87020-900, Brazil

    Erika Meyer, Jéssica Mendes Bonato, Marco Aurélio Mori, Bianca Andretto Mattos, Humberto Milani & Rúbia Maria Weffort de Oliveira

  2. Department of Pharmacology, School of Medicine, USP, Av. Bandeirantes, Ribeirão Preto, São Paulo, 14015-000, Brazil

    Francisco Silveira Guimarães & Alline Cristina de Campos

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  1. Erika Meyer
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  2. Jéssica Mendes Bonato
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  4. Bianca Andretto Mattos
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  5. Francisco Silveira Guimarães
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  8. Rúbia Maria Weffort de Oliveira
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Contributions

EM and RMWO conceived and designed the experiments with inputs from ACC. EM performed behavioral tests, western blot, and Golgi analysis. She wrote the first draft of the manuscript. EM and JMB conducted the animals’ surgeries. BAM performed the immunohistochemistry. MAM performed data analysis. FSG and HM helped with statistical analysis and data interpretation. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rúbia Maria Weffort de Oliveira.

Ethics declarations

Research Involving Human Participants and/and or Animals

The local Ethics Committee on Animal Experimentation of the State University of Maringá approved the experimental procedures in accordance with the guidelines of the U.S. National Institutes of Health and Brazilian College for Animal Experimentation (animal license number: CEUA 1555230316).

Ethics Approval and Consent to Participate

This study was carried out at the State University of Maringá in strict accordance with the Brazilian College of Animal Experimentation (COBEA) recommendations. Animal experiments were approved by the local Ethics Committee on Animal Experimentation of the State University of Maringá (animal license number: CEUA 1555230316).

Consent for Publication

All of the co-authors approved the final version of the manuscript and agreed to submit it to Molecular Neurobiology.

Competing Interests

FSG is a co-inventor (Mechoulam R, JC, Guimaraes FS, AZ, JH, Breuer A) of the patent “Fluorinated CBD compounds, compositions, and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US No. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.”

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Meyer, E., Bonato, J.M., Mori, M.A. et al. Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity. Mol Neurobiol 58, 5338–5355 (2021). https://doi.org/10.1007/s12035-021-02479-7

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