Role of Oleanolic acid in maintaining BBB integrity by targeting p38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid hemorrhage

Han, Yuwei; Liu, Xiujuan; Zhao, Ying; Li, Xiaoming

doi:10.1016/j.ejphar.2018.09.018

Cited by 35 publications

(20 citation statements)

References 38 publications

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“…Furthermore, p38 MAPK activates Src family kinase regulates BBB permeability in response to VEGF. p38MAPK/VEGF/Src kinase pathway is also involved in BBB disruption and vasogenic edema formation via inflammation-associated BBB dysfunction in subarchnoid hemorrhage (Han et al, 2018), ischemic stroke (Liang et al, 2009) and cold-induced brain injury, but not experimental pneumococcal meningitis (Paul et al, 2007). Therefore, it is not excluded the possibilities that p38 MAPK-VEGF axis would lead to SE-induced vasogenic edema formation activating the cPLA2 and Src pathways.…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

Park

Choi

Kong

et al. 2019

Front. Cell. Neurosci.

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Status epilepticus (SE, a prolonged seizure activity) impairs brain-blood barrier (BBB) integrity, which results in secondary complications following SE. The non-integrin 67-kDa laminin receptor (67-kDa LR) plays a role in cell adherence to laminin (a major glycoprotein component in basement membrane), and participates laminin-mediated signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK). Thus, we investigated the role of 67-kDa LR in SE-induced vasogenic edema formation in the rat piriform cortex (PC). SE diminished 67-kDa LR expression, but increased laminin expression, in endothelial cells accompanied by the reduced SMI-71 (a rat BBB barrier marker) expression. Astroglial 67-kDa LR expression was also reduced in the PC due to massive astroglial loss. 67-kDa LR neutralization led to serum extravasation in the PC concomitant with the reduced SMI-71 expression. 67-kDa LR neutralization also decreased expressions of dystrophin and aquaporin-4 (AQP4). In addition, it increased p38 MAPK phosphorylation and expressions of vascular endothelial growth factor (VEGF), laminin and endothelial nitric oxide synthase (eNOS), which were abrogated by SB202190, a p38 MAPK inhibitor. Therefore, our findings indicate that 67-kDa LR dysfunction may disrupt dystrophin-AQP4 complex, which would evoke vasogenic edema formation and subsequent laminin over-expression via activating p38 MAPK/VEGF axis.

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Section: Discussionmentioning

confidence: 99%

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

Park

Choi

Kong

et al. 2019

Front. Cell. Neurosci.

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“…Fibrin cleaved from fibrinogen has been reported to play a potential role in neuroinflammation and microglial activation (Lim-Hing and Rincon, 2017). Iron, degraded from hemoglobin, is one of most important factors among various components for hemorrhagic stroke-induced BBB hyperpermeability (Hua et al, 2007;Gomes et al, 2014), which is supported by ICH/SAH studies revealing alleviated brain edema with administration of the iron chelator, deferoxamine (Lee et al, 2010;Okauchi et al, 2010;Yu et al, 2014), or a heme oxygenase (HO) inhibitor (Wagner et al, 2000;Han et al, 2018). HO plays a critical role in the degradation of heme and the release of free ferrous iron (Kamat et al, 2019).…”

Section: Mechanisms Of Bbb Dysfunction Secondary To Hemorrhagic Strokementioning

confidence: 99%

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

Fang

Gao

Wang

et al. 2020

Front. Cell. Neurosci.

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Hemorrhagic stroke is a life-threatening neurological disease characterized by high mortality and morbidity. Various pathophysiological responses are initiated after blood enters the interstitial space of the brain, compressing the brain tissue and thus causing cell death. Recently, three new programmed cell deaths (PCDs), necroptosis, pyroptosis, and ferroptosis, were also found to be important contributors in the pathophysiology of hemorrhagic stroke. Additionally, blood-brain barrier (BBB) dysfunction plays a crucial role in the pathophysiology of hemorrhagic stroke. The primary insult following BBB dysfunction may disrupt the tight junctions (TJs), transporters, transcytosis, and leukocyte adhesion molecule expression, which may lead to brain edema, ionic homeostasis disruption, altered signaling, and immune infiltration, consequently causing neuronal cell death. This review article summarizes recent advances in our knowledge of the mechanisms regarding these new PCDs and reviews their contributions in hemorrhagic stroke and potential crosstalk in BBB dysfunction. Numerous studies revealed that necroptosis, pyroptosis, and ferroptosis participate in cell death after subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Endothelial dysfunction caused by these three PCDs may be the critical factor during BBB damage. Also, several signaling pathways were involved in PCDs and BBB dysfunction. These new PCDs (necroptosis, pyroptosis, ferroptosis), as well as BBB dysfunction, each play a critical role after hemorrhagic stroke. A better understanding of the interrelationship among them might provide us with better therapeutic targets for the treatment of hemorrhagic stroke.

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“…31,32 In a rat model of subarachnoid hemorrhage, oleanolic acid significantly reduced blood-brain barrier permeability and relieved brain edema by increasing protein expression of tight junctions and adherent junctions. 33 Oleanolic acid inhibits angiogenesis during the development of retinopathy of prematurity model in the mouse retina. 34 Systemic administration of TUDCA suppresses laser-induced CNV formation and blocks fluorescein leakage in the retinas.…”

Section: Tgr5-mediated Endothelial Permeability Under Tnf-α Stimulationmentioning

confidence: 99%

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

et al. 2020

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Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus‐induced microvascular dysfunction in retinas is largely unknown. Herein, enzyme‐linked immunosorbent assay was used for analyzing bile acid (BA) profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin (STZ)‐induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion, and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho‐associated coiled‐coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways. Here we show that bile acids were downregulated during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes‐induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF‐α on endothelial cell proliferation, migration, and permeability in vitro. In contrast, knockdown of TGR5 by siRNA aggravated TNF‐α‐induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF‐α stimulation. Taken together, our findings suggest that insufficient BA signaling plays an important pathogenic role in the development of DR. Upregulation or activation of TGR5 may inhibit RhoA/ROCK‐dependent actin remodeling and represent an important therapeutic intervention for DR.

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Role of Oleanolic acid in maintaining BBB integrity by targeting p38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid hemorrhage

Cited by 35 publications

References 38 publications

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

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