Normobaric Hyperoxia Slows Blood–Brain Barrier Damage and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in Cerebral Ischemia

Background and Purpose— Prolonged ischemia causes blood–brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue P O 2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. Methods— Rats were exposed to NBO (100% O 2 ) or normoxia (21% O 2 ) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. Results— NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). Conclusions— Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke.

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Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model

BioMed Research International ◽

10.1155/2018/8943210 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 17

Author(s):

YinZhong Ma ◽

Li Li ◽

LingLei Kong ◽

ZhiMei Zhu ◽

Wen Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Plasminogen Activator ◽

Blood Brain Barrier ◽

Time Window ◽

Tissue Type ◽

Stroke Model ◽

Thromboembolic Stroke ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Therapeutic Time Window

Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PA infusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor α (PDGFRα) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.

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Tissue-type Plasminogen Activator Acts as a Cytokine That Triggers Intracellular Signal Transduction and Induces Matrix Metalloproteinase-9 Gene Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m504988200 ◽

2005 ◽

Vol 281 (4) ◽

pp. 2120-2127 ◽

Cited By ~ 126

Author(s):

Kebin Hu ◽

Junwei Yang ◽

Sakae Tanaka ◽

Steven L. Gonias ◽

Wendy M. Mars ◽

...

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Matrix Metalloproteinase ◽

Plasminogen Activator ◽

Tissue Type ◽

Intracellular Signal Transduction ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Intracellular Signal ◽

Metalloproteinase 9

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The 4.5-Hour Time Window for Intravenous Thrombolysis With Intravenous Tissue-Type Plasminogen Activator Is Not Firmly Established

Stroke ◽

10.1161/strokeaha.113.002701 ◽

2014 ◽

Vol 45 (3) ◽

pp. 914-915 ◽

Cited By ~ 5

Author(s):

Lawrence R. Wechsler

Keyword(s):

Plasminogen Activator ◽

Time Window ◽

Intravenous Thrombolysis ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator

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Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway

Neural Plasticity ◽

10.1155/2020/8851089 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Xin-chang Zhang ◽

Ya-hui Gu ◽

Wen-tao Xu ◽

Yang-yang Song ◽

Ao Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Edema ◽

Time Window ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Hemorrhagic Transformation ◽

Male Rat ◽

Tight Junction Proteins ◽

Therapeutic Time Window ◽

Junction Proteins

Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.

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