Deficiency in Serine Protease Inhibitor Neuroserpin Exacerbates Ischemic Brain Injury by Increased Postischemic Inflammation

Mathias Gelderblom,Tim Magnus,Markus Glatzel,Peter Ludewig,Christian Bernreuther,Susanne Krasemann,Melanie Neumann,Priyadharshini Arunachalam,Christian Gerloff,Thomas Langmann

doi:10.1371/journal.pone.0063118

Mathias Gelderblom, Tim Magnus + Show 8 more

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https://doi.org/10.1371/journal.pone.0063118

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Abstract

The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns−/−) mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns−/− mice. Our results show excessive microglial activation in Ns−/− mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.

Highlights

The therapeutic administration of plasminogen activator in cerebral ischemia aims at the re-canalization of the occluded vessel [1]
Ns2/2 mice showed a significantly increased infarct size compared to wild type animals from 38.365.6 mm3 to 61.0623.8 mm3 (Fig. 1A)
The neurological disability three days following cerebral ischemia was significantly worse in Ns2/2 mice compared to wt mice (Fig. 1B)

Summary

Introduction

The therapeutic administration of plasminogen activator (tPA) in cerebral ischemia aims at the re-canalization of the occluded vessel [1]. TPA is a serine protease that converts plasminogen to plasmin leading to subsequent fibrin degradation. Beside its beneficial thrombolytic activity in the vascular compartment, tPA contributes to an ischemia induced increase in permeability of the neurovascular unit at the blood brain interface with subsequent development of harmful brain edema [5]. TPA aggravates excitotoxic neuronal cell death via interaction with Nmetyl-D-aspartate (NMDA) receptors, degradation of components of the extracellular matrix, activation of microglial cells, and induction of pro-inflammatory cytokines (for review see [4]). A molecule inhibiting adverse tPA effects in stroke is neuroserpin, a serine protease inhibitor specific to the brain [6]

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