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

• Published in: Translational stroke research Vol. 12; no. 1; pp. 72 - 86
• Main Authors: Trout, Amanda L., Kahle, Michael P., Roberts, Jill M., Marcelo, Aileen, de Hoog, Leon, Boychuk, Jeffery A., Grupke, Stephen L., Berretta, Antonio, Gowing, Emma K., Boychuk, Carie R., Gorman, Amanda A., Edwards, Danielle N., Rutkai, Ibolya, Biose, Ifechukwude J., Ishibashi-Ueda, Hatsue, Ihara, Masafumi, Smith, Bret N., Clarkson, Andrew N., Bix, Gregory J.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-02-2021; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Antibodies; Bats; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Cardiology; Cell growth; Cells, Cultured; Heparan sulfate; Heparan Sulfate Proteoglycans - administration & dosage; Heparan Sulfate Proteoglycans - biosynthesis; Humans; Ischemia; Male; Mice; Mice, Inbred C57BL; Mortality; Neurogenesis; Neurogenesis - drug effects; Neurogenesis - physiology; Neurology; Neuroprotection - drug effects; Neuroprotection - physiology; Neurosciences; Neurosurgery; Organ Culture Techniques; Original; Original Article; Protein Domains; Stroke - metabolism; Stroke - pathology; Stroke - prevention & control; Surgery; Vascular Surgery; Veins & arteries; Stroke; Integrin; Neurorepair; Neurogenesis; Perlecan
• ISSN: 1868-4483; 1868-601X
• DOI: 10.1007/s12975-020-00800-5

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.