Plasminogen deficiency causes reduced corticospinal axonal plasticity and functional recovery after stroke in mice.

Zhongwu Liu,Yi Li,Michael Chopp,Yisheng Cui,Jianyong Qian

doi:10.1371/journal.pone.0094505

Zhongwu Liu, Yi Li + Show 3 more

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https://doi.org/10.1371/journal.pone.0094505

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Journal: PloS one	Publication Date: Apr 14, 2014
Citations: 9	License type: CC BY 4.0

Affiliation: Henry Ford Hospital, Oakland University, Michigan United

Abstract

Tissue plasminogen activator (tPA) has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg) into plasmin. In this study, using plasminogen knockout (Plg-/-) mice and their Plg-native littermates (Plg+/+), we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group) were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo). A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticospinal tract (CST). Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p<0.01). BDA-positive axonal density of the CST originating from the contralesional cortex in the denervated side of the cervical gray matter was significantly reduced in Plg-/- mice compared with Plg+/+ mice (p<0.05). The behavioral outcome was highly correlated with the midline-crossing CST axonal density (R2>0.82, p<0.01). Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord.

Highlights

One of the most common impairments after stroke is hemiparesis of the contralateral body side to the affected cerebral hemisphere
In both Plg+/+ and Plg-/- mice subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo), a large lesion area was observed in the cerebral cortex, corpus callosum, striatum, basal ganglia and thalamus at 28 days after stroke (Figure 1A)
corticospinal tract (CST) axonal remodeling highly correlates with behavioral outcome after stroke To test whether contralesional CST axonal remodeling functionally contributes to neurological outcome after stroke, we examined the correlation of behavioral outcome with the midlinecrossing CST axonal density in the denervated side of the cervical cord 28 days after MCAo

Summary

Introduction

One of the most common impairments after stroke is hemiparesis of the contralateral body side to the affected cerebral hemisphere. As hemiparesis after stroke is a consequence of interruption of motor signals from the motor cortex to the spinal motoneurons, reestablishment of the corticospinal innervation provides a physical substrate for functional recovery. Our prior studies have demonstrated that axonal remodeling of the corticospinal tract (CST) contributes to neurological recovery after stroke in rodents [1]. Bone marrow stromal cells (MSCs) significantly enhanced CST axonal outgrowth in the denervated spinal cord, and thereby improved motor functional recovery of the stroke-impaired forelimb [2]. Recent in vitro and in vivo data suggest that endogenous tPA mediates MSC induced neurite outgrowth and functional recovery after stroke [3,4,5]. Subacute (7 day post stroke) intranasal tPA delivery into the rodent brain promoted CST axonal remodeling and behavioral outcome after stroke [6]

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