scholarly journals Subacute Intranasal Administration of Tissue Plasminogen Activator Promotes Neuroplasticity and Improves Functional Recovery following Traumatic Brain Injury in Rats

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e106238 ◽  
Author(s):  
Yuling Meng ◽  
Michael Chopp ◽  
Yanlu Zhang ◽  
Zhongwu Liu ◽  
Aaron An ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Intranasal Administration ◽  
Tissue Plasminogen

scholarly journals Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

2018 ◽  
Vol 115 (39) ◽  
pp. E9230-E9238 ◽  
Author(s):  
Yuguo Xia ◽  
Hongjian Pu ◽  
Rehana K. Leak ◽  
Yejie Shi ◽  
Hongfeng Mu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Knockout Mice ◽  
White Matter Integrity ◽  
Tissue Plasminogen

Recombinant tissue plasminogen activator (tPA) is a Food and Drug Administration-approved thrombolytic treatment for ischemic stroke. tPA is also naturally expressed in glial and neuronal cells of the brain, where it promotes axon outgrowth and synaptic plasticity. However, there are conflicting reports of harmful versus neuroprotective effects of tPA in acute brain injury models. Furthermore, its impact on white matter integrity in preclinical traumatic brain injury (TBI) has not been thoroughly explored, although white matter disruption is a better predictor of long-term clinical outcomes than focal lesion volumes. Here we show that the absence of endogenous tPA in knockout mice impedes long-term recovery of white matter and neurological function after TBI. tPA-knockout mice exhibited greater asymmetries in forepaw use, poorer sensorimotor balance and coordination, and inferior spatial learning and memory up to 35 d after TBI. White matter damage was also more prominent in tPA knockouts, as shown by diffusion tensor imaging, histological criteria, and electrophysiological assessments of axon conduction properties. Replenishment of tPA through intranasal application of the recombinant protein in tPA-knockout mice enhanced neurological function, the structural and functional integrity of white matter, and postinjury compensatory sprouting in corticofugal projections. tPA also promoted neurite outgrowth in vitro, partly through the epidermal growth factor receptor. Both endogenous and exogenous tPA protected against white matter injury after TBI without increasing intracerebral hemorrhage volumes. These results unveil a previously unappreciated role for tPA in the protection and/or repair of white matter and long-term functional recovery after TBI.

scholarly journals Erythrocyte-Bound Tissue Plasminogen Activator is Neuroprotective in Experimental Traumatic Brain Injury

2009 ◽  
Vol 26 (9) ◽  
pp. 1585-1592 ◽  
Author(s):  
Sherman C. Stein ◽  
Kumkum Ganguly ◽  
Caitlin M. Belfield ◽  
Xiangsheng Xu ◽  
Edward W. Swanson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen ◽  
Experimental Traumatic Brain Injury

scholarly journals Erythrocyte-bound Tissue Plasminogen Activator (tPA) is Neuroprotective in Experimental Traumatic Brain Injury

2009 ◽  
pp. 090330061141047
Author(s):  
Sherman C Stein ◽  
Kumkum Ganguly ◽  
Caitlin M Belfield ◽  
Xiangsheng Xu ◽  
Edward W. Swanson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen ◽  
Experimental Traumatic Brain Injury

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

Tissue plasminogen activator and hemorrhagic brain injury

2002 ◽  
pp. 181-191
Author(s):  
Minoru Asahi ◽  
Rick M. Dijkhuizen ◽  
Xiaoying Wang ◽  
Bruce R. Rosen ◽  
Eng H. Lo
Keyword(s):  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen

Abstract WP109: Subacute Intranasal Administration of Tissue Plasminogen Activator Increases Corticospinal Tract Plasticity and Functional Recovery After Stroke in Mice

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jian-Yong Qian ◽  
Michael Chopp ◽  
Ning Chen ◽  
Zhongwu Liu
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Gray Matter ◽  
Functional Recovery ◽  
Corticospinal Tract ◽  
Neurological Recovery ◽  
Saline Control ◽  
Lesion Volume ◽  
Therapeutic Benefits ◽  
Tissue Plasminogen

In addition to thrombolysis, tissue plasminogen activator (tPA) is involved in synaptic plasticity, dendritic remodeling and axonal outgrowth in the developing and injured CNS. We have demonstrated that tPA administered intranasally during the subacute phase after stroke enhanced neurological recovery in rats. In the present study, we examined the therapeutic benefits of intranasal tPA treatment on corticospinal tract (CST) axonal remodeling in adult mice with transgenic yellow fluorescent protein (YFP) labeling specifically in the CST subjected to permanent middle cerebral artery occlusion (MCAo). Animals were treated intranasally with 4 doses of human recombinant tPA (300 ug/dose) or saline (control) at day 7, 9, 11 and 13 after MCAo (n=10/group), respectively. An adhesive-removal test and a single-pellet reaching test were performed at 1, 3, and 7 days after MCAo, and weekly thereafter to monitor functional recovery. Animals were euthanized 4 weeks after stroke. There was no difference in lesion volume between control and tPA-treated groups (p>0.05). Compared with saline treated animals, significant functional improvements were evident in mice treated with tPA (p<0.05), as well as significantly increased CST axonal density in the denervated side of the gray matter of the cervical cord (p<0.01). We also isolated, and cultured primary embryonic YFP neurons with tPA at concentrations of 0.065, 0.65, 2.0 and 6.5 μg/ml, respectively, for 3 days, and observed that tPA dose-dependently increased neurite length and number (P<0.05). Our data suggest that delayed tPA intranasal treatment provides therapeutic benefits for neurological recovery after stroke by, at least in part, promoting CST axonal remodeling in the denervated spinal cord gray matter.

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