Tissue-Type Plasminogen Activator has a Neuroprotective Effect in the Ischemic Brain Mediated by Neuronal TNF-α

Abstract

Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissuetype plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor-a. This effect, mediated by plasmin and the N-methyl-D-aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance.

Rescue Thrombectomy in Large Vessel Occlusion Strokes Leads to Better Outcomes than Intravenous Thrombolysis Alone: A ‘Real World' Applicability of the Recent Trials

“…Thus, any potential benefit of IV rt-PA in this setting appears to be unrelated to its reperfusion mechanism. This finding is consistent with a recent study demonstrating lower rates of infarct growth in fully reperfused patients who received IV rt-PA prior to thrombectomy than in those who did not and supports the recent experimental data suggesting a neuroprotective effect to rt-PA [14,15]. Our study also adds to the increasing body of evidence demonstrating the safety of rescue endovascular therapy following intravenous thrombolysis, as no difference in the rates of sICH were seen amongst NASA patients who did and those who did not receive IV rt-PA (11.9 vs. 9.0%, p = 0.5) [1,3,4,5,6,16].…”

Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons

“…The serine proteinase tissue-type plasminogen activator (tPA) is abundantly expressed in neurons (Samson and Medcalf, 2006), and its rapid release from the presynaptic terminal promotes the development of synaptic plasticity (Qian et al, 1993, Seeds et al, 1995, Muller and Griesinger, 1998, Pawlak et al, 2003), neuronal survival (Echeverry et al, 2010, Haile et al, 2012, Wu et al, 2013a), adaptation to metabolic stress (Wu et al, 2012, Wu et al, 2013b), and neuroglial coupling (An et al, 2014). TPA is found in the presynaptic terminal of cerebral cortical neurons, either intermixed with clear-core SVs of the reserve and recycling pools, or in direct contact with the presynaptic membrane (Wu, 2015).…”

Review paper Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?

“…Apart from thrombolysis during the first hours, which can be given only to a small percentage of patients, no effective regenerative treatment to improve functional recovery exists in the postischemic period [17,35,36]. The persistence of neural stem cells and neurogenesis in the brain after birth, first suggested in 1912 [2], is accepted now.…”

“…To our best knowledge, amongst the current reviews concerning postischemic hippocampal neurogenesis [30,54], diet and brain ischemia and diet and postischemic hippocampal neurogenesis, our review is the first to put together neurogenesis in the hippocampus and postischemic brain neurodegeneration through the effects of dietary influence on both phenomena, in this manner providing a unique and new perspective on the state of postischemic hippocampal neurogenesis. Given that these days there are no effective therapies for postischemic brain neurodegeneration, and no regenerative therapy exists [17,35,36], dietary intervention may be an option to help delay disease progression.…”

“…A few clinically active, yet not fully effective, therapies such as acetylsalicylic acid, statins and tissue type plasminogen activator are available for ischemic stroke [17,35,36]. In the wake of this neurodegenerative pathology, with limited medical therapies, alternative treatments are required which can control the progression of postischemic neurodegeneration.…”