A cannabidiol aminoquinone derivative activates the PP2A/B55[alpha]/HIF pathway and shows protective effects in a murine model of traumatic brain injury

• Published in: Journal of neuroinflammation 2022-07, Vol.19 (1)
• Main Authors: Navarrete, Carmen, García-Martín, Adela, Correa-Sáez, Alejandro, Prados, María E, Fernández, Francisco, Pineda, Rafael, Mazzone, Massimiliano, Ãlvarez-Benito, Marina, Calzado, Marco A, Muéoz, Eduardo
• Format: Article
• Language: English
• Subjects: Animal experimentation; Brain; Evaluation; Injuries
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02540-9

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 PPAR[gamma]/CB.sub.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/B55[alpha] in HIF activation was analyzed using siRNA for B55[alpha]. 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/B55[alpha] pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/[alpha]-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/B55[alpha]/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and