A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury

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Abstract

Background

Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood–brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB ₂ agonist that also activates the hypoxia inducible factor (HIF) pathway. VCE-004.8 shows potent antifibrotic, anti-inflammatory and neuroprotective activities and it is now in Phase II clinical trials for systemic sclerosis and multiple sclerosis. Herein, we investigated the mechanism of action of VCE-004.8 in the HIF pathway and explored its efficacy in a preclinical model of TBI.

Methods

Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI.

Results

Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood–brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area.

Conclusions

This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12974-022-02540-9.

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Most cited references 81

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3D Slicer as an image computing platform for the Quantitative Imaging Network.

Andriy Y Fedorov, Reinhard Beichel, Jayashree Kalpathy-Cramer … (2012)

Quantitative analysis has tremendous but mostly unrealized potential in healthcare to support objective and accurate interpretation of the clinical imaging. In 2008, the National Cancer Institute began building the Quantitative Imaging Network (QIN) initiative with the goal of advancing quantitative imaging in the context of personalized therapy and evaluation of treatment response. Computerized analysis is an important component contributing to reproducibility and efficiency of the quantitative imaging techniques. The success of quantitative imaging is contingent on robust analysis methods and software tools to bring these methods from bench to bedside. 3D Slicer is a free open-source software application for medical image computing. As a clinical research tool, 3D Slicer is similar to a radiology workstation that supports versatile visualizations but also provides advanced functionality such as automated segmentation and registration for a variety of application domains. Unlike a typical radiology workstation, 3D Slicer is free and is not tied to specific hardware. As a programming platform, 3D Slicer facilitates translation and evaluation of the new quantitative methods by allowing the biomedical researcher to focus on the implementation of the algorithm and providing abstractions for the common tasks of data communication, visualization and user interface development. Compared to other tools that provide aspects of this functionality, 3D Slicer is fully open source and can be readily extended and redistributed. In addition, 3D Slicer is designed to facilitate the development of new functionality in the form of 3D Slicer extensions. In this paper, we present an overview of 3D Slicer as a platform for prototyping, development and evaluation of image analysis tools for clinical research applications. To illustrate the utility of the platform in the scope of QIN, we discuss several use cases of 3D Slicer by the existing QIN teams, and we elaborate on the future directions that can further facilitate development and validation of imaging biomarkers using 3D Slicer. Copyright © 2012 Elsevier Inc. All rights reserved.

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Estimating the global incidence of traumatic brain injury

Michael Dewan, Abbas Rattani, Saksham Gupta … (2018)

Traumatic brain injury (TBI)—the “silent epidemic”—contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. Open-source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64–74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650–1947) and Europe (1012 cases, 95% CI 911–1113) and least in Africa (801 cases, 95% CI 732–871) and the Eastern Mediterranean (897 cases, 95% CI 771–1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. Sixty-nine million (95% CI 64–74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe.

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Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

Andrew Maas, David Menon, P David Adelson … (2017)

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Author and article information

Contributors

Eduardo Muñoz: fi1muble@uco.es

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 9 July 2022

Publication date PMC-release: 9 July 2022

Publication date Collection: 2022

Volume: 19

Electronic Location Identifier: 177

Affiliations

[1 ]Emerald Health Pharmaceuticals, San Diego, USA

[2 ]GRID grid.411901.c, ISNI 0000 0001 2183 9102, Maimonides Biomedical Research Institute of Córdoba, University of Córdoba, ; Avda Menéndez Pidal s/n, 14004 Córdoba, Spain

[3 ]GRID grid.411901.c, ISNI 0000 0001 2183 9102, Cellular Biology, Physiology and Immunology Department, , University of Cordoba, ; Córdoba, Spain

[4 ]GRID grid.411349.a, ISNI 0000 0004 1771 4667, Hospital Universitario Reina Sofía, ; Córdoba, Spain

[5 ]VivaCell Biotechnology España, Córdoba, Spain

[6 ]GRID grid.411349.a, ISNI 0000 0004 1771 4667, FEA Radiodiagnóstico, Sección de Neurorradiología Diagnóstica. Hospital Universitario Reina Sofía, ; Córdoba, Spain

[7 ]Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB-KULeuven, 3000 Louvain, Belgium

[8 ]GRID grid.411349.a, ISNI 0000 0004 1771 4667, Unidad de Radiodiagnóstico Y Cáncer de Mama, Hospital Universitario Reina Sofía, ; Córdoba, Spain

Article

Publisher ID: 2540

DOI: 10.1186/s12974-022-02540-9

PMC ID: 9270745

PubMed ID: 35810304

SO-VID: 1261359a-0bd0-48af-99c5-4727092cec7f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 7 March 2022

Date accepted : 30 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;

Award ID: PID2020-114753RB-I00

Award Recipient : Carmen Navarrete Adela García-Martín Eduardo Muñoz

Funded by: Junta de A

Award ID: P18-RTJ-4163

Award Recipient : Rafael Pineda

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: traumatic brain injury,protein phosphatase 2a,hypoxia-inducible factor,prolyl-hydroxylases,brain–blood barrier,neuroprotection

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: traumatic brain injury, protein phosphatase 2a, hypoxia-inducible factor, prolyl-hydroxylases, brain–blood barrier, neuroprotection

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury

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Abstract

Background

Methods

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Conclusions

Supplementary Information

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Neuronal Signaling

Most cited references 81

3D Slicer as an image computing platform for the Quantitative Imaging Network.

Estimating the global incidence of traumatic brain injury

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

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