Simvastatin in traumatic brain injury: Effect on brain edema mechanisms

Béziaud, Tiphaine; Chen, Xiao Ru; Shafey, Nelly El; Fréchou, Magalie; Teng, Fei; Palmier, B.; Beray-Berthat, Virginie; Soustrat, Mathieu; Margaill, Isabelle; Plotkine, Michel; Marchand-Leroux, Catherine; Besson, Valérie

doi:10.1097/ccm.0b013e3182227e4a

Cited by 48 publications

(24 citation statements)

References 48 publications

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“…4,5 ICAM-1, typically expressed on vascular and immune system cells, induced proinflammatory effects, such as amplifying leukocyte recruitment signals and enhancing neutrophil infiltration into the brain, which exacerbates the brain injury in ICH models. 6,7,21 The main function of VSMCs is to regulate tissue perfusion through graded contraction. Importantly, VSMC display a remarkable plasticity by converting among different phenotypes during some pathologies, a process referred to as VSMC phenotypic transformation.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Yang

Miao

et al. 2016

Critical Care Medicine

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Objective Platelet-derived growth factor-BB (PDGF-BB) activates platelet-derived growth factor receptor-β (PDGFR-β) and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1 (ICAM-1), which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of PDGF-BB/PDGFR-β following intracerebral hemorrhage (ICH)-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell (VSMC) phenotypic transformation followed by increased ICAM-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the PDGF-BB/PDGFR-β system subsequent to ICH. Methods Brain injury was induced by autologous arterial blood (bICH) or plasmin injection into mouse brains. Small interfering RNA targeting PDGFR-β was administered 24 hours before ICH. A PDGFR antagonist, Gleevec, was administered following ICH. A mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2) inhibitor (KKKALNRQLGVAA) was delivered with PDGF-BB in naïve animals. PDGF-BB was injected with a plasmin inhibitor (ɛ-Aminocaproic acid, EACA) in ICH mice. Plasmin-injected mice were given PDGFR-β small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, Western blots and immunofluorescence were evaluated. Results PDGFR-βsiRNA-attenuated SMemb and ICAM-1 expression and neutrophil infiltration at 24 hours post-injury, and reduced neurological deficits and brain edema at 24 and 72 hours following ICH. The PDGFR antagonist, Gleevec, reduced SMemb and ICAM-1 expression. PDGFR-β activation led to increased expression of ICAM-1 and was reversed by KKKALNRQLGVAA in naïve mice. Plasmin inhibition suppressed PDGFR-β activation and neutrophil infiltration, whereas exogenous PDGF-BB increased PDGFR-β activation, regardless of plasmin inhibition. PDGFR-β siRNA decreased the expression of ICAM-1 by plasmin injection. Interpretation The PDGF-BB/PDGFR-β system contributes to neuro-inflammation through VSMC phenotypic transformation near the hematoma via the p38 MAPK/MK2 pathway following ICH. Plasmin is hypothesized to be upstream of the proposed neuro-inflammatory system. The therapeutic intervention targeting the PDGF-BB/PDGFR-β is a novel strategy to prevent plasmin-induced brain injury following ICH.

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Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Yang

Miao

et al. 2016

Critical Care Medicine

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“…These effects are associated with EC barrier protection conferred by simvastatin and mediated by differential Rho GTPase activation (2), inhibition of superoxide generation via reduced nicotinamide adenine dinucleotide phosphate oxidase (3), and the upregulation of integrin-b4 (2). However, circumstantial evidence of a role for claudin-5 in ALI protection by statins is suggested by increased expression of EC claudin-5 in response to statin treatment (7,29). Moreover, a functional link between statins and claudin-5 is suggested by statin regulation of integrin-b1 (30,31), which has been identified as a mediator of increased vascular permeability via effects on claudin-5 (32).…”

Section: Discussionmentioning

confidence: 99%

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

Chen

Sharma

Rizzo

et al. 2014

Am J Respir Cell Mol Biol

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The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 mM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and b-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPSinduced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.

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“…Animal models of TBI have shown that statin therapy may reduce posttraumatic brain edema by preserving blood brain barrier function, preventing damage to tight junctions, and reducing neutrophil infiltration into the brain parenchyma [71]. Simvastatin therapy in a murine model of TBI expressing human beta-amyloid peptide has been shown to blunt TBI-induced increases in beta-amyloid peptide, while reducing hippocampal tissue damage and microglial activation, thus potentially decreasing the risk of TBI-associated dementia [72].…”

Section: Traumatic Brain Injurymentioning

confidence: 98%

Mechanisms and Clinical Evidence of the Pleiotropic Effects of the Hydroxy-Methyl-Glutaryl-CoA Reductase Inhibitors in Central Nervous System Disorders: A Comprehensive Review

Yanuck

Mihos

Santana

2012

International Journal of Neuroscience

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The hydroxy-methyl-glutaryl-CoA reductase inhibitors, better known as statins, are principally used in the treatment of hyperlipidemia and play a pivotal role in the primary and secondary prevention of atherosclerotic heart disease and stroke. Evidence also exists for the potential benefits from statin use in a variety of other disease processes, conferred via their non-lipid lowering properties, which are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropic effects of statins in neurological disorders. Emphasis is placed on the discussion of randomized, placebo-controlled trials, and their importance in further elucidating this interesting phenomenon.

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Simvastatin in traumatic brain injury: Effect on brain edema mechanisms

Abstract: Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity.

Cited by 48 publications

References 48 publications

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

Mechanisms and Clinical Evidence of the Pleiotropic Effects of the Hydroxy-Methyl-Glutaryl-CoA Reductase Inhibitors in Central Nervous System Disorders: A Comprehensive Review

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