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

Lemarchand, Eloïse; Maubert, Eric; Haelewyn, Benoît; Ali, Carine; Rubio, Marina; Vivien, Denis

doi:10.1038/cdd.2015.76

Cited by 37 publications

(34 citation statements)

References 49 publications

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“…CSPG has been implicated in the inhibition of spontaneous axonal plasticity after TBI (30,31). The neurotrophic effects of tPA are thought to be partly mediated by the epidermal growth factor receptor (EGFR) (32,33). As expected, CSPG decreased the length of tau + axons in neurons in a concentration-dependent manner (SI Appendix, Fig.…”

Section: Intranasal Delivery Of Recombinant Tpa Rescues Neurological mentioning

confidence: 56%

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

Xia

Leak

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Recombinant tissue plasminogen activator (tPA) is a Food and Drug Administration-approved thrombolytic treatment for ischemic stroke. tPA is also naturally expressed in glial and neuronal cells of the brain, where it promotes axon outgrowth and synaptic plasticity. However, there are conflicting reports of harmful versus neuroprotective effects of tPA in acute brain injury models. Furthermore, its impact on white matter integrity in preclinical traumatic brain injury (TBI) has not been thoroughly explored, although white matter disruption is a better predictor of long-term clinical outcomes than focal lesion volumes. Here we show that the absence of endogenous tPA in knockout mice impedes long-term recovery of white matter and neurological function after TBI. tPA-knockout mice exhibited greater asymmetries in forepaw use, poorer sensorimotor balance and coordination, and inferior spatial learning and memory up to 35 d after TBI. White matter damage was also more prominent in tPA knockouts, as shown by diffusion tensor imaging, histological criteria, and electrophysiological assessments of axon conduction properties. Replenishment of tPA through intranasal application of the recombinant protein in tPA-knockout mice enhanced neurological function, the structural and functional integrity of white matter, and postinjury compensatory sprouting in corticofugal projections. tPA also promoted neurite outgrowth in vitro, partly through the epidermal growth factor receptor. Both endogenous and exogenous tPA protected against white matter injury after TBI without increasing intracerebral hemorrhage volumes. These results unveil a previously unappreciated role for tPA in the protection and/or repair of white matter and long-term functional recovery after TBI.

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Section: Intranasal Delivery Of Recombinant Tpa Rescues Neurological mentioning

confidence: 56%

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

Xia

Leak

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The growth factor domain of tPA confers antiapoptotic capacity through its binding to the EGF receptor. 23,24 However, AG1478 (5 μM), an EGFR tyrosine kinase inhibitor, did not prevent the beneficial effect of tPA during OGD reox ( Figure 5b, 31% of neuronal death for tPA under OGD reox ; 26% for tPA+AG1478 under OGD reox ), excluding a role for EGF receptor. tPA can also interact through its finger domain with LRP-1 (type 1 low-density lipoprotein receptor-related protein) to promote NFκB activation 25 and Akt phosphorylation.…”

Section: Resultsmentioning

confidence: 96%

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

et al. 2017

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The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2α branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation.

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“…However, more recent studies have shown potential benefits of tPA for the treatment of ischemic stroke. As evidence of its beneficial effects, tPA has been shown to play a critical role in inhibiting neuronal apoptosis and promoting functional recovery in late phase after stroke 15–18 . tPA has been shown to exert opposite effects at different time points on the same target 19 (e.g., extracellular matrix, NMDA receptors).…”

Section: Tpa: Biology Thrombolytic Mechanism and Pleiotropic Funmentioning

confidence: 99%

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

Liu

Feng

Jin

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA. Areas covered We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed. Expert opinion Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.

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

Cited by 37 publications

References 49 publications

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

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