The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury

Higashida, Tetsuhiro; Kreipke, Christian W.; Rafols, José A.; Peng, Changya; Schafer, Steven; Schafer, Patrick; Ding, Jamie Y.; Dornbos, David; Li, Xiaohua; Guthikonda, Murali; Rossi, Noreen F.; Ding, Yuchuan

doi:10.3171/2010.6.jns10207

Cited by 255 publications

(154 citation statements)

References 39 publications

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“…MIN doses of 1 mg/kg were reported to attenuate BBB breakdown and the formation of cerebral edema following injury [11]. While many studies administered drug shortly after injury, some have been published reporting MIN administration beginning at least one day following experimental ischemic injury and continuing daily for an extended period of time [10, 17] including a human stroke study that reported efficacy when MIN was administered up to 24 hours after the ischemic event, though few patients received drug at this time [16].…”

Section: Discussionmentioning

confidence: 99%

Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury

Kelso

Scheff

et al. 2011

Neuroscience Letters

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The biochemical sequelae that follow traumatic brain injury (TBI) are numerous and affect many different brain functions at different points of time as the secondary cascades progress. The complexity of the resulting pathophysiology is such that a singular therapeutic intervention may not provide adequate benefit and a combination of drugs targeting different pathways may be needed. Two of the most widely studied injury mechanisms are oxidative stress and inflammation. Numerous studies have suggested that pharmacological agents targeting either of these pathways may produce an improvement in histological and functional outcome measures. We hypothesized that combining melatonin, a potent antioxidant, with minocycline, a bacteriostatic agent that also inhibit microglia, would provide better neuroprotection than either agent used alone. To test this hypothesis, we subjected anesthetized adult male rats to a 1.5 mm controlled cortical impact and administered melatonin or vehicle in the acute post-injury period followed by daily minocycline or vehicle injections beginning the following day in a 2×2 study design. The animals were allowed to recover for 5 days before undergoing Morris water maze (MWM) testing to assess cognitive functioning following injury. There was no significant difference in MWM performance between the vehicle, melatonin, minocycline, or combination treatments. Following sacrifice and histological examination for neuroprotection, we did not observe a significant difference between the groups in the amount of cortical tissue that was spared nor was there a significant difference in [ 3 H]-PK11195 binding, a marker for activated microglia. These results suggest that neither drug has therapeutic efficacy, however dosing and/or administration issues may have played a role.

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Section: Discussionmentioning

confidence: 99%

Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury

Kelso

Scheff

et al. 2011

Neuroscience Letters

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“…Studies have further shown that activation of MMP-2/9 and inducible nitric oxide synthase (iNOS) accelerates the digestion of tight junction-associated protein complex and extracellular matrix along with basal lamina and the inflammatory response, respectively, has been proposed to partake in TBI [39] [40]. Moreover, the inhibition of MMPs or iNOS by specific inhibitors was shown to contribute to the decrease of TBI to some extent [40].…”

Section: Stein Et Al Demonstrated That the Translocation Of Hmgb1 Inmentioning

confidence: 99%

High Mobility Group Box 1 and Traumatic Brain Injury

Richard¹,

Wu²,

Su³

et al. 2017

JBBS

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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after TBI. As a prototypical danger associated molecular patterns (DAMP), HMGB1 is released from necrotic neurons via a NR2B-mediated mechanism during TBI. The secretion of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response. HMGB1 is clinically associated with elevated intracranial pressure (ICP) in patients and functionally promoted cerebral edema after TBI. The detrimental effects of HMGB1 is mediated at least in part between activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel aquaporin-4 (AQP4). Anti-HMGB1mAb remarkably inhibited fluid percussion-induced brain edema by inhibiting HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression and improvement of motor function. Our review demonstrates the pathological role of HMGB1 as well as the possible therapeutic valve of HMGB1 in patients with TBI.

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“…On the one hand, several previous studies have demonstrated that HIF-1α is protective to endothelial or epithelial barrier function under some pathophysiological conditions such as hypoxia or inflammation [33,34,35,36,37]. On the other hand, growing evidence demonstrates that HIF-1α is deleterious to endothelial or epithelial barrier function during hypoxic, ischemic or inflammatory insult [15,25,26,38,39,40,41]. Chemical inhibition of HIF-1α by HIF-1α inhibitors such as YC-1, 2-methoxyestradiol and oligomycin attenuates the endothelial or epithelial barrier dysfunction induced by hypoxia, ischemia or proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that HIF-1α is involved in barrier dysfunction by inducing the expression of HIF-1 target genes such as vascular endothelial growth factor, inducible nitric oxide synthase [38,40,46], aquaporin-4, matrix metalloproteinase-9 [39], macrophage migration inhibitory factor [47], as well as by repressing the expression of vasodilator-stimulated phosphoprotein [48]. However, the activation of MLCK, which in turn leads to an increase of MLC phosphorylation, has been reported to play a critical role in endothelial and intestinal barrier dysfunction induced by hypoxia or inflammation [21,22,23,24,28,29,31,49].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Hypoxia-Inducible Factor-1a Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

Wang

Qi²,

Sun³

et al. 2013

Cell Physiol Biochem

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Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α) in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER). The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1), zonular occludens-1 (ZO-1), occludin, and myosin light chain kinase (MLCK) in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

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The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury

Abstract: The data support the notion that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular pathway cascade involving AQP-4 and MMP-9. Pharmacological blockade of this pathway in patients with TBI may provide a novel therapeutic strategy.

Cited by 255 publications

References 39 publications

Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury

Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury

High Mobility Group Box 1 and Traumatic Brain Injury

Overexpression of Hypoxia-Inducible Factor-1a Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

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