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.
Highlights
Stroke is a leading cause of death and disability [1]
We recently demonstrated that administration of recombinant perlecan domain V (DV) 24 h after transient middle cerebral artery occlusion (MCAo) in mice and rats promotes the brain neurorepair
Clinical relevance of DV to human ischemic stroke was investigated by DV immunohistochemistry on the brains of several stroke patients (Online Resource Table 2) at different post-stroke day (PSD) time points (PSD 1 to post-stroke (or sham) day (PSD) 90)
Summary
Stroke is a leading cause of death and disability [1]. The only FDA-approved pharmaceutical for ischemic stroke, tissue plasminogen activator (tPA), has a narrow therapeutic window [2]. While thrombectomy is standard of care, clinical outcome lag behind improved recanalization rates [3]. Many experimental stroke therapies have a limited therapeutic window and/or have failed in clinical trials [4, 5], suggesting a critical need for stroke therapies with a broader therapeutic window. DV was neuroprotective and improved functional outcome in both young and aged mice [6]. DV crosses the blood-brain barrier and drives VEGF-mediated processes of neuroprotection and angiogenesis [7], while peri-infarct astrogliosis is increased acutely but suppressed chronically [8]. Together, this suggests DV may be a novel therapeutic for stroke
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