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Obacunone alleviates ischemia-induced blood-brain barrier disruption and brain injury via targeting MIF signaling

ABSTRACT: Blood-brain barrier (BBB) breakdown is one of the hallmarks of stroke pathology, which is characterized by the death of brain capillary endothelial cells and the disassembly of intercellular tight junction. Damaged BBB is associated with poor stroke prognosis, and few treatment of BBB breakdown is applicable. Obacunone (Oba) is a highly oxygenated triterpenoid with known pharmacological activities on mitigating colonic epithelial cell injury, however whether Oba could be effective to endothelial cell integrity remains unknown. In the present study, with the use of transient middle cerebral artery occlusion (tMCAO) mice model, we found that gavage Oba significantly alleviated tMCAO-induced BBB leakage, brain injury and neurological deficit. In the oxygen-glucose deprivation (OGD) model of mice brain microvascular endothelial cells (MBMECs), synergistic application of Oba and ISO-1 revealed the protective effect of Oba against MBMECs monolayer leakage via inhibiting MBMECs-derived macrophage migration inhibitory factor (MIF). In mechanism, with the use of bulk RNA sequencing and a battery of molecular approaches, we found that inhibition of MIF by Oba attenuated the activation of pro-apoptotic signals, including P38 and RIPK1, and promoted the distribution of tight junction ZO-1 onto MBMECs membrane, which was accompanied with the upregulation of intracellular LCN2. In consistent, pharmacological inhibition of LCN2 by ZINC00640089 protected against OGD-induced MBMECs death and monolayer leakage. These results collectively conclude that Oba alleviates ischemia-induced BBB breakdown and brain injury via, at least partially, inhibiting MIF-mediated endothelial cell death and intercellular junction loss. Oba may represent a therapeutic candidate for neurological disorders caused by cerebral stroke.

ORGANISM(S): Mus musculus

PROVIDER: GSE317846 | GEO | 2026/05/08

REPOSITORIES: GEO

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Project description:Background: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood-brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.

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Obacunone alleviates ischemia-induced blood-brain barrier disruption and brain injury via targeting MIF signaling

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