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'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.

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…Laminin G-like (LG) modules in laminin, perlecan and agrin mediate stabilising ECM interactions that are crucial to basement membrane assembly and nerve cell function [ 297 , 298 , 299 , 300 , 301 ]. Perlecan contains three LG domains, and as previously mentioned, displays neurogenic and neuroprotective properties and promise in the repair of the BBB following ischaemic stroke and in the treatment of vascular dementia [ 255 , 256 , 257 , 302 , 303 , 304 , 305 , 306 ]. Agrin and collagen XVIII also contain multiple laminin-G domains which are interactive with other basement membrane components.…”

Neurogenesis After Stroke: A Therapeutic Perspective

“…In addition, proteolysis of matrix proteins such as perlecan has been implicated in promoting neurogenesis in post-stroke brains [40]. Its c-terminal domain V (DV) is thought to be the active component leading to neurogenesis as well as angiogenesis at the infarct and peri-infarct area [41,42]. Using neurospheres and fetal cortical neurons in vitro, Trout and colleagues [42] showed that perlecan DV also promoted differentiation into mature neurons as well as neurite The neuroblasts formed before and after the stroke migrate to the site of injury, influenced by chemokines and cytokines secreted by resident and activated microglia, reactive astrocytes, etc.…”

“…Its c-terminal domain V (DV) is thought to be the active component leading to neurogenesis as well as angiogenesis at the infarct and peri-infarct area [41,42]. Using neurospheres and fetal cortical neurons in vitro, Trout and colleagues [42] showed that perlecan DV also promoted differentiation into mature neurons as well as neurite The neuroblasts formed before and after the stroke migrate to the site of injury, influenced by chemokines and cytokines secreted by resident and activated microglia, reactive astrocytes, etc. The neuroblasts then differentiate into newborn neurons coupled with angiogenesis at the site of injury, giving rise to mature neurons extension.…”

The Stroke-Induced Blood-Brain Barrier Disruption: Current Progress of Inspection Technique, Mechanism, and Therapeutic Target

“…In experimental ischemic stroke, a perlecan level was downregulated by 43–63% within 2 h from onset [ 127 , 128 ]. In contrast, post-stroke perlecan domain V treatment promoted brain angiogenesis via the induction of vascular endothelial growth factor (VEGF) from brain endothelial cells [ 129 ]. Treatment with exogenous recombinant domain V of human perlecan after ischemic stroke exerted neuroprotective effect as well as infarction volume reduction in both wild-type mice and perlecan-deficient mice [ 127 , 130 ].…”