Poloxamer 188 Protects Neurons against Ischemia/Reperfusion Injury through Preserving Integrity of Cell Membranes and Blood Brain Barrier

Gu, Jin-Hua; Ge, Jingping; Li, Mei; Xu, Haidong; Wu, Feng; Qin, Zheng‐Hong

doi:10.1371/journal.pone.0061641

Cited by 68 publications

(80 citation statements)

References 32 publications

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“…MMP-9 activation can lead to the degradation of tight junction proteins, such as occludin and ZO-1, and thus increase BBB permeability following injury (21). The present study identified that the expression of MMP-9 was enhanced following the induction of TBI, in accordance with previous reports (20,21). In addition, the expression of the tight junction proteins occludin and ZO-1 was significantly downregulated following TBI.…”

Section: Discussionsupporting

confidence: 91%

“…Previous studies have suggested a strong association between oxidative stress and MMP-9 in the pathophysiology of BBB damage following TBI (18,19), as oxidative stress has been reported to trigger molecular cascades that mediate MMP-9 activation (20). MMP-9 activation can lead to the degradation of tight junction proteins, such as occludin and ZO-1, and thus increase BBB permeability following injury (21).…”

Section: Discussionmentioning

confidence: 99%

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Roles of elevated 20‑HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury

Wang

Yuan

et al. 2018

Mol Med Report

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Breakdown of the blood brain barrier (BBB) is a secondary injury following traumatic brain injury (TBI) and can lead to the development of brain edema. However, the factors that contribute to the disruption of the BBB and increase the severity of brain edema in TBI remain to be elucidated. 20‑hydroxyeicosatetraenoic acid (20‑HETE) is a metabolite of arachidonic acid. The inhibition of 20‑HETEsynthesis by HET0016 has been suggested as a strategy to decrease brain edema. The present study aimed to investigate whether the elevated production of 20‑HETE in cerebral tissue may contribute to BBB breakdown and increase the severity of brain edema in rats with TBI. BBB permeability was quantified using dynamic contrast‑enhanced magnetic resonance imaging and brain edema was measured according to brain water content. Superoxide production in injured tissue was also assessed. Liquid chromatography‑mass spectrometry was used to evaluate 20‑HETE production in injured tissue. Western blot analysis was used to assess the expression of occludin, zonula occludens (ZO)‑1, matrix metalloproteinase (MMP)‑9, and proteins of the c‑Jun N‑terminal kinase (JNK) pathway. A total of 3, 24 and 72 h following the induction of TBI, 20‑HETE levels, BBB permeability and brain edema were identified to be increased, accompanied by an increase in superoxide production. Conversely, superoxide dismutase levels, in addition to the total antioxidative capability were decreased. In addition, the expression of MMP‑9 and proteins of the JNK pathway was upregulated, whereas the expression of occludin and ZO‑1 was observed to be suppressed. These results suggested that 20‑HETE may aggravate BBB disruption following TBI, via enhancing the expression of MMP‑9 and tight junction proteins. Furthermore, oxidative stress and the JNK signaling pathway may be involved in BBB dysregulation. In conclusion, the results of the present demonstrated that the production of 20‑HETE was increased in cerebral tissue following traumatic injury, thus suggesting that it may contribute to the compromise of BBB integrity and the development of brain edema.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Roles of elevated 20‑HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury

Wang

Yuan

et al. 2018

Mol Med Report

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“…Some inflammatory cytokines were closely related to the expression of matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4). Cerebral ischemia has been shown to induce activation of MMP9, which is associated with impairment of the neurovasculature, resulting in BBB leakage [7][8][9][10] . A generalized increase in cellular MMP9 immunoreactivity contributes to neuronal injury after ischemia reperfusion 11 .…”

Section: Introductionmentioning

confidence: 99%

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats

Guo

Feng

Miao

et al. 2014

Immunopharmacology and Immunotoxicology

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Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

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“…This may prevent unregulated exchange of ions between the extracellular and intracellular compartments thereby preventing cellular injury and apoptosis [32, 33]. P188 has been shown to protect neurons [34] and skeletal muscle [35, 36] against ischemia/reperfusion injury. It also preserves blood-brain barrier integrity during traumatic brain injury thereby reducing brain edema and neuronal apoptosis [37].…”

Section: Discussionmentioning

confidence: 99%

Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17min of untreated cardiac arrest

Bartos¹,

Matsuura²,

Sarraf³

et al. 2015

Resuscitation

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Objective Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15 minutes of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. Methods Following 17 minutes of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR + ITD + sevoflurane + P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. Results Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48 hours), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48 hours). Conclusions Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17 minutes of untreated cardiac arrest in pigs.

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Poloxamer 188 Protects Neurons against Ischemia/Reperfusion Injury through Preserving Integrity of Cell Membranes and Blood Brain Barrier

Cited by 68 publications

References 32 publications

Roles of elevated 20‑HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury

Roles of elevated 20‑HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats

Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17min of untreated cardiac arrest

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