Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice

Amanda L. Trout; Michael P. Kahle; Jill M. Roberts; Aileen Marcelo; Leon de Hoog; Jeffery A. Boychuk; Stephen L. Grupke; Antonio Berretta; Emma K. Gowing; Carie R. Boychuk; Amanda A. Gorman; Danielle N. Edwards; Ibolya Rutkai; Ifechukwude J. Biose; Hatsue Ishibashi-Ueda; Masafumi Ihara; Bret N. Smith; Andrew N. Clarkson; Gregory J. Bix

doi:10.1007/s12975-020-00800-5

Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice

Amanda L. Trout, Michael P. Kahle, Jill M. Roberts, Aileen Marcelo, Leon de Hoog, Jeffery A. Boychuk, Stephen L. Grupke, Antonio Berretta, Emma K. Gowing, Carie R. Boychuk, Amanda A. Gorman, Danielle N. Edwards, Ibolya Rutkai, Ifechukwude J. Biose, Hatsue Ishibashi-Ueda, Masafumi Ihara, Bret N. Smith, Andrew N. Clarkson, Gregory J. Bix

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

The extracellular matrix fragment perlecan domain V is neuroprotective and functionally restorative following experimental stroke. As neurogenesis is an important component of chronic post-stroke repair, and previous studies have implicated perlecan in developmental neurogenesis, we hypothesized that domain V could have a broad therapeutic window by enhancing neurogenesis after stroke. We demonstrated that domain V is chronically increased in the brains of human stroke patients, suggesting that it is present during post-stroke neurogenic periods. Furthermore, perlecan deficient mice had significantly less neuroblast precursor cells after experimental stroke. Seven-day delayed domain V administration enhanced neurogenesis and restored peri-infarct excitatory synaptic drive to neocortical layer 2/3 pyramidal neurons after experimental stroke. Domain V’s effects were inhibited by blockade of α2β1 integrin, suggesting the importance of α2β1 integrin to neurogenesis and domain V neurogenic effects. Our results demonstrate that perlecan plays a previously unrecognized role in post-stroke neurogenesis and that delayed DV administration after experimental stroke enhances neurogenesis and improves recovery in an α2β1 integrin-mediated fashion. We conclude that domain V is a clinically relevant neuroprotective and neuroreparative novel stroke therapy with a broad therapeutic window.

Original language	English
Pages (from-to)	72-86
Number of pages	15
Journal	Translational Stroke Research
Volume	12
Issue number	1
DOIs	https://doi.org/10.1007/s12975-020-00800-5
State	Published - Feb 2021

Bibliographical note

Funding Information:
This work was funded by the National Institutes of Health R21 NS079960 (GB), the National Institutes of Health R21 NS088608 (BS), the National Institutes of Health R01 NS092552 (BS), the American Heart Associtation (MK), the Sir Charles Hercus Fellowship from the Health Research Council of New Zealand, a Health Research Council of New Zealand project grant and the Royal Society of New Zealand Marsden Fund (AC), and the Neurological Foundation of New Zealand project grant (AB & AC). Acknowledgments

Publisher Copyright:
© 2020, The Author(s).

Keywords

Integrin
Neurogenesis
Neurorepair
Perlecan
Stroke

ASJC Scopus subject areas

Neuroscience (all)
Clinical Neurology
Cardiology and Cardiovascular Medicine

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10.1007/s12975-020-00800-5

Cite this

Trout, A. L., Kahle, M. P., Roberts, J. M., Marcelo, A., de Hoog, L., Boychuk, J. A., Grupke, S. L., Berretta, A., Gowing, E. K., Boychuk, C. R., Gorman, A. A., Edwards, D. N., Rutkai, I., Biose, I. J., Ishibashi-Ueda, H., Ihara, M., Smith, B. N., Clarkson, A. N., & Bix, G. J. (2021). Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice. Translational Stroke Research, 12(1), 72-86. https://doi.org/10.1007/s12975-020-00800-5

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title = "Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice",

abstract = "The extracellular matrix fragment perlecan domain V is neuroprotective and functionally restorative following experimental stroke. As neurogenesis is an important component of chronic post-stroke repair, and previous studies have implicated perlecan in developmental neurogenesis, we hypothesized that domain V could have a broad therapeutic window by enhancing neurogenesis after stroke. We demonstrated that domain V is chronically increased in the brains of human stroke patients, suggesting that it is present during post-stroke neurogenic periods. Furthermore, perlecan deficient mice had significantly less neuroblast precursor cells after experimental stroke. Seven-day delayed domain V administration enhanced neurogenesis and restored peri-infarct excitatory synaptic drive to neocortical layer 2/3 pyramidal neurons after experimental stroke. Domain V{\textquoteright}s effects were inhibited by blockade of α2β1 integrin, suggesting the importance of α2β1 integrin to neurogenesis and domain V neurogenic effects. Our results demonstrate that perlecan plays a previously unrecognized role in post-stroke neurogenesis and that delayed DV administration after experimental stroke enhances neurogenesis and improves recovery in an α2β1 integrin-mediated fashion. We conclude that domain V is a clinically relevant neuroprotective and neuroreparative novel stroke therapy with a broad therapeutic window.",

keywords = "Integrin, Neurogenesis, Neurorepair, Perlecan, Stroke",

author = "Trout, {Amanda L.} and Kahle, {Michael P.} and Roberts, {Jill M.} and Aileen Marcelo and {de Hoog}, Leon and Boychuk, {Jeffery A.} and Grupke, {Stephen L.} and Antonio Berretta and Gowing, {Emma K.} and Boychuk, {Carie R.} and Gorman, {Amanda A.} and Edwards, {Danielle N.} and Ibolya Rutkai and Biose, {Ifechukwude J.} and Hatsue Ishibashi-Ueda and Masafumi Ihara and Smith, {Bret N.} and Clarkson, {Andrew N.} and Bix, {Gregory J.}",

note = "Funding Information: This work was funded by the National Institutes of Health R21 NS079960 (GB), the National Institutes of Health R21 NS088608 (BS), the National Institutes of Health R01 NS092552 (BS), the American Heart Associtation (MK), the Sir Charles Hercus Fellowship from the Health Research Council of New Zealand, a Health Research Council of New Zealand project grant and the Royal Society of New Zealand Marsden Fund (AC), and the Neurological Foundation of New Zealand project grant (AB & AC). Acknowledgments Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

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doi = "10.1007/s12975-020-00800-5",

language = "English",

volume = "12",

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Trout, AL, Kahle, MP, Roberts, JM, Marcelo, A, de Hoog, L, Boychuk, JA, Grupke, SL, Berretta, A, Gowing, EK, Boychuk, CR, Gorman, AA, Edwards, DN, Rutkai, I, Biose, IJ, Ishibashi-Ueda, H, Ihara, M, Smith, BN, Clarkson, AN & Bix, GJ 2021, 'Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice', Translational Stroke Research, vol. 12, no. 1, pp. 72-86. https://doi.org/10.1007/s12975-020-00800-5

TY - JOUR

T1 - Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice

AU - Trout, Amanda L.

AU - Kahle, Michael P.

AU - Roberts, Jill M.

AU - Marcelo, Aileen

AU - de Hoog, Leon

AU - Boychuk, Jeffery A.

AU - Grupke, Stephen L.

AU - Berretta, Antonio

AU - Gowing, Emma K.

AU - Boychuk, Carie R.

AU - Gorman, Amanda A.

AU - Edwards, Danielle N.

AU - Rutkai, Ibolya

AU - Biose, Ifechukwude J.

AU - Ishibashi-Ueda, Hatsue

AU - Ihara, Masafumi

AU - Smith, Bret N.

AU - Clarkson, Andrew N.

AU - Bix, Gregory J.

N1 - Funding Information: This work was funded by the National Institutes of Health R21 NS079960 (GB), the National Institutes of Health R21 NS088608 (BS), the National Institutes of Health R01 NS092552 (BS), the American Heart Associtation (MK), the Sir Charles Hercus Fellowship from the Health Research Council of New Zealand, a Health Research Council of New Zealand project grant and the Royal Society of New Zealand Marsden Fund (AC), and the Neurological Foundation of New Zealand project grant (AB & AC). Acknowledgments Publisher Copyright: © 2020, The Author(s).

PY - 2021/2

Y1 - 2021/2

N2 - The extracellular matrix fragment perlecan domain V is neuroprotective and functionally restorative following experimental stroke. As neurogenesis is an important component of chronic post-stroke repair, and previous studies have implicated perlecan in developmental neurogenesis, we hypothesized that domain V could have a broad therapeutic window by enhancing neurogenesis after stroke. We demonstrated that domain V is chronically increased in the brains of human stroke patients, suggesting that it is present during post-stroke neurogenic periods. Furthermore, perlecan deficient mice had significantly less neuroblast precursor cells after experimental stroke. Seven-day delayed domain V administration enhanced neurogenesis and restored peri-infarct excitatory synaptic drive to neocortical layer 2/3 pyramidal neurons after experimental stroke. Domain V’s effects were inhibited by blockade of α2β1 integrin, suggesting the importance of α2β1 integrin to neurogenesis and domain V neurogenic effects. Our results demonstrate that perlecan plays a previously unrecognized role in post-stroke neurogenesis and that delayed DV administration after experimental stroke enhances neurogenesis and improves recovery in an α2β1 integrin-mediated fashion. We conclude that domain V is a clinically relevant neuroprotective and neuroreparative novel stroke therapy with a broad therapeutic window.

AB - The extracellular matrix fragment perlecan domain V is neuroprotective and functionally restorative following experimental stroke. As neurogenesis is an important component of chronic post-stroke repair, and previous studies have implicated perlecan in developmental neurogenesis, we hypothesized that domain V could have a broad therapeutic window by enhancing neurogenesis after stroke. We demonstrated that domain V is chronically increased in the brains of human stroke patients, suggesting that it is present during post-stroke neurogenic periods. Furthermore, perlecan deficient mice had significantly less neuroblast precursor cells after experimental stroke. Seven-day delayed domain V administration enhanced neurogenesis and restored peri-infarct excitatory synaptic drive to neocortical layer 2/3 pyramidal neurons after experimental stroke. Domain V’s effects were inhibited by blockade of α2β1 integrin, suggesting the importance of α2β1 integrin to neurogenesis and domain V neurogenic effects. Our results demonstrate that perlecan plays a previously unrecognized role in post-stroke neurogenesis and that delayed DV administration after experimental stroke enhances neurogenesis and improves recovery in an α2β1 integrin-mediated fashion. We conclude that domain V is a clinically relevant neuroprotective and neuroreparative novel stroke therapy with a broad therapeutic window.

KW - Integrin

KW - Neurogenesis

KW - Neurorepair

KW - Perlecan

KW - Stroke

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AN - SCOPUS:85083051676

SN - 1868-4483

VL - 12

SP - 72

EP - 86

JO - Translational Stroke Research

JF - Translational Stroke Research

IS - 1

ER -

Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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