Tissue plasminogen activator protects hippocampal neurons from oxygen-glucose deprivation injury

Flavin, Michael P.; Zhao, Gang

doi:10.1002/1097-4547(20010301)63:5<388::aid-jnr1033>3.0.co;2-t

Cited by 37 publications

(15 citation statements)

References 29 publications

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“…2004) can all be achieved despite the inhibition of the tPA catalytic site. Together with the previous similar observations during oxygen and glucose deprivation (Flavin and Zhao 2001), our present results of an anti‐apoptotic effect of tPA independent of its proteolytic activity, strongly support the notion of a ‘cytokine‐like’ or even ‘neurotrophic‐like’ function of tPA.…”

Section: Discussionsupporting

confidence: 91%

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Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

Liot

Roussel

Lebeurrier

et al. 2006

Journal of Neurochemistry

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Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.

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Section: Discussionsupporting

confidence: 91%

“…2005; Takahashi et al . 2005), anti‐apoptotic (Flavin and Zhao 2001) or even no (Ferrer et al . 2001) effect of tPA.…”

Section: Discussionmentioning

confidence: 99%

Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

Liot

Roussel

Lebeurrier

et al. 2006

Journal of Neurochemistry

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“…We found that in contrast to tPA-induced early preconditioning, the effect of tPA on delayed preconditioning is inhibited by NMDAR antagonists, and that tPA induces delayed tolerance against KA-induced neuronal death, indicating that tPAinduced delayed preconditioning is mediated by attenuation of the excitotoxic injury. Whereas our results conflict with previous observations by others showing that genetic deficiency of tPA pro- tects hippocampal neurons from the intracerebral injection of KA (9), they agree with other reports that indicate a protective effect of tPA against KA-induced neuronal death (31,38). However, as our results also demonstrate, the effect of tPA on KA-induced cell death is highly dependent on the characteristics of the experimental paradigm.…”

Section: Discussionsupporting

confidence: 56%

Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus

Echeverry¹,

Wu²,

Haile³

et al. 2010

J. Clin. Invest.

116

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The best-known function of the serine protease tissue-type plasminogen activator (tPA) is as a thrombolytic enzyme. However, it is also found in structures of the brain that are highly vulnerable to hypoxia-induced cell death, where its association with neuronal survival is poorly understood. Here, we have demonstrated that hippocampal areas of the mouse brain lacking tPA activity are more vulnerable to neuronal death following an ischemic insult. We found that sublethal hypoxia, which elicits tolerance to subsequent lethal hypoxic/ischemic injury in a natural process known as ischemic preconditioning (IPC), induced a rapid release of neuronal tPA. Treatment of hippocampal neurons with tPA induced tolerance against a lethal hypoxic insult applied either immediately following insult (early IPC) or 24 hours later (delayed IPC). tPA-induced early IPC was independent of the proteolytic activity of tPA and required the engagement of a member of the LDL receptor family. In contrast, tPA-induced delayed IPC required the proteolytic activity of tPA and was mediated by plasmin, the NMDA receptor, and PKB phosphorylation. We also found that IPC in vivo increased tPA activity in the cornu ammonis area 1 (CA1) layer and Akt phosphorylation in the hippocampus, as well as ischemic tolerance in wild-type but not tPA-or plasminogen-deficient mice. These data show that tPA can act as an endogenous neuroprotectant in the murine hippocampus.

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“…19,39 Accordingly, in a model of global ischemia and in agreement with our present study, a beneficial effect of both endogenous and exogenous tPA was reported by Yepes' group, an effect also confirmed in cultured hippocampal neurons subjected to OGD. 19 These data are in agreement with another study from the same group, demonstrating a beneficial effect of endogenous tPA against ischemic paradigms, both in vitro and in vivo.…”

supporting

confidence: 92%

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

et al. 2015

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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.

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Tissue plasminogen activator protects hippocampal neurons from oxygen-glucose deprivation injury

Cited by 37 publications

References 29 publications

Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus

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

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