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Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.

ABSTRACT: In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.

SUBMITTER: Lemarchand E

PROVIDER: S-EPMC4815983 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.

Lemarchand E E Maubert E E Haelewyn B B Ali C C Rubio M M Vivien D D

Cell death and differentiation 20150612 1

In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mic ...[more]

PMID: 26068590

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Project description:BackgroundThe necessity for rapid evaluation and treatment of acute ischemic stroke with intravenous tPA (tissue-type plasminogen activator) may increase the risk of administrating tPA to patients presenting with noncerebrovascular conditions that closely resemble stroke (stroke mimics). However, there are limited data on thrombolysis safety in stroke mimics.Methods and resultsUsing data from the Get With The Guidelines-Stroke Registry, we identified 72 582 patients with suspected ischemic stroke treated with tPA from 485 US hospitals between January 2010 and December 2017. We documented the use of tPA in stroke mimics, defined as patients who present with stroke-like symptoms, but after workup are determined not to have suffered from a stroke or transient ischemic attack, and compared characteristics and outcomes in stroke mimics versus those with ischemic stroke. Overall, 3.5% of tPA treatments were given to stroke mimics. Among them, 38.2% had a final nonstroke diagnoses of migraine, functional disorder, seizure, and electrolyte or metabolic imbalance. Compared with tPA-treated true ischemic strokes, tPA-treated mimics were younger (median 54 versus 71 years), had a less severe National Institute of Health Stroke Scale (median 6 versus 8), and a lower prevalence of cardiovascular risk factors, except for a higher prevalence of prior stroke/transient ischemic attack (31.3% versus 26.1%, all P<0.001). The rate of symptomatic intracranial hemorrhage was lower in stroke mimics (0.4%) as compared with 3.5% in ischemic strokes (adjusted odds ratio, 0.29; 95% CI, 0.17-0.50). In-hospital mortality rate was significantly lower in stroke mimics (0.8% versus 6.2%, adjusted odds ratio, 0.31; 95% CI, 0.20-0.49). Patients with stroke mimics were more likely to be discharged to home (83.8% versus 49.3%, adjusted odds ratio, 2.97; 95% CI, 2.59-3.42) and to ambulate independently at discharge (78.6% versus 50.6%, adjusted odds ratio, 1.86; 95% CI, 1.61-2.14).ConclusionsIn this large cohort of patients treated with tPA, relatively few patients who received tPA for presumed stroke were ultimately not diagnosed with a stroke or transient ischemic attack. The complication rates associated with tPA in stroke mimics were low. Despite the potential risk of administering tPA to stroke mimics, opportunity remains for continued improvement in the rapid and accurate diagnosis and treatment of ischemic stroke.

Dataset Information

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.

Publications

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.

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