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

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/CB2 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.

Transcranial direct current stimulation promotes angiogenesis and improves neurological function via the OXA-TF-AKT/ERK signaling pathway in traumatic brain injury

“…Presently, it is recognized that primary injuries resulting from mechanical forces are seldom curable; however, there exists potential for ameliorating and reversing secondary injuries subsequent to TBI. This has spurred an escalating focus on the issue in recent years [ 33 ]. In this study, we introduced a breakthrough discovery: tDCS promotes angiogenesis at the injury site by upregulating the OXA-TF-AKT/ERK signaling pathway, thereby contributing to neurological recovery after brain trauma.…”

Etrinabdione (VCE-004.8), a B55α activator, promotes angiogenesis and arteriogenesis in critical limb ischemia

“…13 In addition, VCE-004.8 is a dual activator of peroxisome proliferator-activated receptor-γ (PPARγ) and cannabinoid type 2 receptors (CB 2 R). 14 VCE-004.8 showed efficacy in preclinical models of traumatic brain injury, 15 multiple sclerosis 13 , bleomycin- and angiotensin-induced models of dermal, lung, cardiac, and kidney fibrosis 14, 16 , metabolic syndrome 17 and stroke 18 .…”

Fecal microbiota transplantation inhibited neuroinflammation of traumatic brain injury in mice via regulating the gut–brain axis

“…Mechanical brain injury initiates inflammatory and neurovascular changes in the brain, which can lead to neuronal injury and death, which is involved in many complex factors such as oxidative stress, inflammation, and apoptosis. Disruption of the blood–brain barrier (BBB) was observed early after TBI, and the inflammatory response might be stimulated by the rapid release of molecular patterns, resulting in a significant local inflammatory response and intensifying brain damage ( Navarrete et al., 2022 ). The neuroinflammatory response following TBI was known to be a key secondary injury factor, which can lead to neuronal damage ( Corrigan et al., 2016 ).…”