The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?

Zhu, Jiayi; Wang, Yan; Xu, Hexiang; Wu, Yulang; Hu, Bo; Jin, Huijuan

doi:10.1007/s00018-019-03005-8

Cited by 25 publications

(26 citation statements)

References 186 publications

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“…Thus, we cannot exclude that the pleiotropic effects of tPA may also contribute to the BBB disruption and HT in this study. Second, tPA is widely expressed in the brain and thought to mediate neuronal death and microglial activation after excitotoxic injury (Sheehan & Tsirka, 2005; Zhu et al., 2019). Therefore, the effects of endogenous and exogenous tPA on the activation of microglia should also be considered as an important influencing factor in our experiments.…”

Section: Discussionmentioning

confidence: 99%

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke

Cheng

Zhao

Xin

et al. 2021

Journal of Neurochemistry

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Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3 hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2 hr after ischemia and continuously monitored for 1 hr after treatment for determining reperfusion.Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24 hr after stroke.12/15-LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood-brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro-inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c-Jun-N-terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12-HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12/15-LOX inhibition and suppression of JNK-mediated microglia/macrophage activation.

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Section: Discussionmentioning

confidence: 99%

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke

Cheng

Zhao

Xin

et al. 2021

Journal of Neurochemistry

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“…Thus, higher serum CysC levels represent more severe inflammatory lesions, uncontrollable vascular remodeling, more vulnerable plaques, or even impaired vascular permeability. All these changes could, at least partially, be responsible for the detached atherosclerotic plaque, vascular reocclusion or angioedema that may eventually cause unfavorable clinical outcomes of IV‐tPA for AIS patients [44‐46].…”

Section: Discussionmentioning

confidence: 99%

Cystatin C is a potential predictor of unfavorable outcomes for cerebral ischemia with intravenous tissue plasminogen activator treatment: A multicenter prospective nested case–control study

Chang

Zou

Xie

et al. 2020

Euro J of Neurology

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Background and purpose The aim of this study was to explore whether cystatin C (CysC) could be used as a potential predictor of clinical outcomes in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV‐tPA). Methods We performed an observational study including a retrospective analysis of data from 125 AIS patients with intravenous thrombolysis. General linear models were applied to compare CysC levels between groups with different outcomes; logistic regression analysis and receiver‐operating characteristic curves were adopted to identify the association between CysC and the therapeutic effects. Results Compared with the "good and sustained benefit" (GSB) outcome group (defined as ≥4‐point reduction in National Institutes of Health Stroke Scale or a score of 0–1 at 24 h and 7 days) and the "good functional outcome" (GFO) group (modified Rankin Scale score 0–2 at 90 days), serum CysC baseline levels were increased in the non‐GSB and non‐GFO groups. Logistic regression analysis found that CysC was an independent negative prognostic factor for GSB (odds ratio [OR] 0.010; p = 0.005) and GFO (OR 0.011; p = 0.021) after adjustment for potential influencing factors. Receiver‐operating characteristic curves showed the CysC‐involved combined models provided credible efficacy for predicting post‐90‐day favorable clinical outcome (area under the curve 0.86; p < 0.001). Conclusions Elevated serum CysC is independently associated with unfavorable clinical outcomes after IV‐tPA therapy in AIS. Our findings provide new insights into discovering potential mediators for neuropathological process or treatment in stroke.

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“…Endothelial cells of microvessels in the brain contribute to the production of tPA, but tPA can also be expressed by glial cells, neurons, and infiltrating leukocytes, implicating a broad spectrum of tPA involvement in the brain. While tPA in the mature brain is detected primarily in neurons, its enzymatic activity is primarily restricted to the hippocampus, amygdala and hypothalamus [63,64] . The discrepancy between the expression of tPA mRNA and its areas of enzymatic activity is consistent with its trafficking and transport to mossy fiber tracts [63,64] .…”

Section: Pas In the Cnsmentioning

confidence: 99%

Review of evidence implicating the plasminogen activator system in blood-brain barrier dysfunction associated with Alzheimer’s disease

Tang¹,

Gorin²,

Lein³

2022

AND

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Elucidating the pathogenic mechanisms of Alzheimer’s disease (AD) to identify therapeutic targets has been the focus of many decades of research. While deposition of extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau have historically been the two characteristic hallmarks of AD pathology, therapeutic strategies targeting these proteinopathies have not been successful in the clinics. Neuroinflammation has been gaining more attention as a therapeutic target because increasing evidence implicates neuroinflammation as a key factor in the early onset of AD disease progression. The peripheral immune response has emerged as an important contributor to the chronic neuroinflammation associated with AD pathophysiology. In this context, the plasminogen activator system (PAS), also referred to as the vasculature’s fibrinolytic system, is emerging as a potential factor in AD pathogenesis. Evolving evidence suggests that the PAS plays a role in linking chronic peripheral inflammatory conditions to neuroinflammation in the brain. While the PAS is better known for its peripheral functions, components of the PAS are expressed in the brain and have been demonstrated to alter neuroinflammation and blood-brain barrier (BBB) permeation. Here, we review plasmin-dependent and -independent mechanisms by which the PAS modulates the BBB in AD pathogenesis and discuss therapeutic implications of these observations.

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The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?

Cited by 25 publications

References 186 publications

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke

Cystatin C is a potential predictor of unfavorable outcomes for cerebral ischemia with intravenous tissue plasminogen activator treatment: A multicenter prospective nested case–control study

Review of evidence implicating the plasminogen activator system in blood-brain barrier dysfunction associated with Alzheimer’s disease

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