Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

Fan, Mengchen; Xu, Haochen; Wang, Lixiang; Luo, Haiyu; Zhu, Ximin; Cai, Ping; Wei, Lixiang; Lu, Lu; Cao, Yongliang; Ye, Rong; Fan, Wenying; Zhao, Bing

doi:10.1038/srep25971

Cited by 25 publications

(19 citation statements)

References 50 publications

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“…A study reported that ADAMTS13 reduced the expression of MMP-9 and an inflammatory factor intercellular cell adhesion molecule-1 (ICAM-1), suggesting that rADAMTS13 protects the brain predominantly by reducing the inflammatory response (53). Similar results were reported by another study (74). Therefore, the combination of rADAMTS 13 and tPA might become a novel treatment for ischemic stroke by diminishing the neurotoxic effect of exogenous tPA.…”

Section: Introductionsupporting

confidence: 93%

ADAMTS13: An Emerging Target in Stroke Therapy

et al. 2019

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Thrombosis is the predominant underlying mechanism of acute ischemic stroke (AIS). Though thrombolysis with tPA has been proven to be effective in treating AIS within the time window, the majority of AIS patients fail to receive tPA due to various reasons. Current medical therapies for AIS have limited efficacy and pose a risk of intracerebral hemorrhage. ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) is a metalloprotease that effectively breaks down the von Willebrand Factor (VWF), a key factor in thrombus formation. Previous studies have proven that dysfunction of ADAMTS13 is associated with many diseases. Recently, ADAMTS13 has been reported to be closely related to stroke. In this review, we briefly described the structure of ADAMTS13 and its role in thrombosis, inflammation, as well as angiogenesis. We then focused on the relationship between ADAMTS13 and AIS, ranging from ischemic stroke occurrence, to AIS treatment and prognosis. Based on research findings from in vitro , animal, and clinical studies, we propose that ADAMTS13 is a potential biomarker to guide appropriate treatment for ischemic stroke and a promising therapeutic agent for tPA resistant thrombi.

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Section: Introductionsupporting

confidence: 93%

ADAMTS13: An Emerging Target in Stroke Therapy

et al. 2019

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“…Using NR2B antagonists and inhibiting, NR2B expression can regulate excitotoxicity induced by glutamate, protect neurons after cerebral infarction, reduce infarction area and promote the recovery of nerve function. [24][25][26] In cognitive-related research, Xu et al 19 used N2B antagonist in the experiment and found that N2B antagonist could effectively inhibit nerve injury and improve spatial memory of rats with cerebral infarction. The results showed that inhibiting NR2B expression was beneficial to cognitive recovery.…”

Section: Discussionmentioning

confidence: 99%

<p>Exercise training increases spatial memory via reducing contralateral hippocampal NMDAR subunits expression in intracerebral hemorrhage rats</p>

Zheng¹,

Zhang²,

Liu

et al. 2019

NDT

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The aim of this study was to explore the effect of exercise training on spatial memory in rats with intracerebral hemorrhage (ICH) and to analyze its related neurobiological mechanisms. Methods: A total of 26 Sprague-Dawley rats were randomly divided into 3 groups: exercise (EX) group undergoing exercise training after ICH, model (MD) group and sham-operated (SM) group. The ICH rats model were induced by infusion of type I collagenase into caudate nucleus of rats. Morris water maze (MWM) test was performed at the same time in three groups to evaluate spatial memory in rats. All rats were sacrificed for evaluation of expression of N-methyl-d-aspartate receptor 1 (NR1) and N-methyl-d-aspartate receptor 2B (NR2B) in the CA3 region of the hippocampus by Western blot. Results: MWM test results showed that the spatial memory of MD group was significantly decreased compared to that of SM operation group (P<0.05), while exercise training significantly improved the spatial memory of rats with cerebral hemorrhage (P<0.05). Western blot analysis showed that exercise training significantly decreased the expression of NR1 and NR2B in CA3 region of the contralateral hippocampus (P<0.05), but there was no significant difference between MD and SM groups (P>0.05). Conclusion: Exercise training improves the spatial memory in the rats with ICH via downregulating NR1 and NR2B expression in CA3 region of the contralateral hippocampus.

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“… 135 136 137 Furthermore, treatment with recombinant ADAMTS13 reduced neurotoxicity induced by rtPA; in a mouse model, recombinant ADAMTS13 in combination with rtPA significantly reduced infarct volume compared with mice treated with rtPA only, reflecting a neuroprotective effect largely mediated by specific NMDA receptor blockade reducing excitotoxic cell death. 138 …”

Section: How Targeting Vwf Could Overcome the Pitfalls Of Current Strmentioning

confidence: 99%

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence

Buchtele

Schwameis

Gilbert³

et al. 2018

Thromb Haemost

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Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification.

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Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

Cited by 25 publications

References 50 publications

ADAMTS13: An Emerging Target in Stroke Therapy

ADAMTS13: An Emerging Target in Stroke Therapy

<p>Exercise training increases spatial memory via reducing contralateral hippocampal NMDAR subunits expression in intracerebral hemorrhage rats</p>

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence

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