Neuroserpin Protects Neurons from Ischemia-Induced Plasmin-Mediated Cell Death Independently of Tissue-Type Plasminogen Activator Inhibition

Abstract

The serine proteinase tissue-type plasminogen activator (tPA) and the serine proteinase inhibitor neuroserpin are both expressed in areas of the brain with the highest vulnerability to hypoxia/ischemia. In vitro studies show that neuroserpin inhibits tPA and, to a lesser extent, urokinase-type plasminogen activator and plasmin. Experimental middle cerebral artery occlusion (MCAO) increases tPA activity and neuroserpin expression in ischemic tissue, and genetic deficiency of tPA or either treatment with or overexpression of neuroserpin decreases the volume of the ischemic lesion following MCAO. These findings have led to the hypothesis that neuroserpin's neuroprotection is mediated by inhibition of tPA's alleged neurotoxic effect. Ischemic preconditioning is a natural adaptive process whereby exposure to a sublethal insult induces tolerance against a subsequent lethal ischemic injury. Here we demonstrate that exposure to sublethal hypoxia/ischemia increases the neuroserpin expression in the hippocampal CA1 layer and cerebral cortex, and that neuroserpin induces ischemic tolerance and decreases the volume of the ischemic lesion following MCAO in wild-type and tPAdeficient (tPA ؊/؊ ) neurons and mice. Plasmin induces neuronal death, and this effect is abrogated by either neuroserpin or the NMDA receptor antagonist MK-801. Neuroserpin also attenuated kainic acid-induced neuronal death. Our data indicate that the neuroprotective effect of neuroserpin is due to inhibition of plasmin-mediated excitotoxin-induced cell death and is independent of neuroserpin's ability to inhibit tPA activity.

Neuroserpin up-regulation in the Alzheimer’s disease brain is associated with elevated thyroid hormone receptor-β1 and HuD expression

“…While these studies provide further support for an association between thyroid hormone and neuroserpin in cognitive deficits, we cannot rule out that the increases seen in neuroserpin, THRβ1 and/or HuD in the Alzheimer’s disease brain occur by mechanisms other than thyroid hormone. For example we cannot rule out that ischemia in the Alzheimer’s disease brain may lead to an increase in neuroserpin expression, since mouse studies with middle cerebral artery occlusion induced ischemia (Wu et al, 2010) showed increased neuroserpin in the hippocampus and cerebral cortex.…”

Serine proteases, serine protease inhibitors, and protease-activated receptors: Roles in synaptic function and behavior

“…Administration of exogenous neuroserpin, by either addition to media for cultured cortical neurons, or direct injection into striatum or cortex is neuroprotective against NMDA-induced excitotoxicity (Lebeurrier et al, 2005). Neuroserpin is also neuroprotective against excitotoxicity in ischemic stroke and seizure models, by both tPA inhibition-dependent and tPA inhibition-independent mechanisms (Cinelli et al, 2001; Wu et al, 2010; Yepes et al, 2002). …”

“…Taken together with observations that neuroserpin overexpressing mice show markedly reduced tPA activity (Cinelli et al, 2001), and that stress-induced changes in CA1 pyramidal cell spine morphology follow upregulation of tPA activity (Pawlak et al, 2003; Pawlak et al, 2005b), this mechanism is consistent with the idea that neuroserpin tightly regulates tPA activity. However, the observation that neuroserpin-deficient mice did not display dysregulated tPA activity (Madani et al, 2003; Wu et al, 2010) suggests that neuroserpin can influence behavior via a mechanism independent of inhibiting tPA activity.…”

Nafamostat Mesilate Improves Neurological Outcome and Axonal Regeneration after Stroke in Rats

“…It has been reported that thrombin, plasmin and kallikrein promote neuron injury and exacerbate glutamate neurotoxicity directly or indirectly [5,6]. For instance, thrombin induces ischemic long-term potentiation (LTP) in hypoxia-treated neurons, impairs the normal LTP [7] and perturbs neurite outgrowth; plasmin contributes to ischemia-induced neuron death [8]; and kallikrein 6 exacerbates glutamate neurotoxicity, implying that serine proteases could be potential targets for neuro-protection following stroke.…”