Despite recent therapeutic advancements,
ischemic stroke remains a major cause of death and disability. It has been previously demonstrated that ~ 85-kDa recombinant human
perlecan domain V (rhPDV) binds to upregulated
integrin receptors (α2β1 and α5β1) associated with neuroprotective and functional improvements in various animal models of
acute ischemic stroke. Recombinant human
perlecan laminin-like globular domain 3 (rhPDVLG3), a 21-kDa C-terminal subdomain of rhPDV, has been demonstrated to more avidly bind to the α2β1
integrin receptor than its parent molecule and consequently was postulated to evoke significant neuroprotective and functional effects. To test this hypothesis, fifty male C57Bl/6 J mice studied in a t-MCAO model were randomly allocated to either rhPDV treatment, rhPDVLG3, or equivalent volume of PBS at the time of reperfusion in a study where all procedures and analyses were conducted blind to treatment. On post-MCAO day 7,
2,3,5-triphenyltetrazolium chloride staining of brain slices was used to quantify
infarct volume. We observed that treatment with rhPDVLG3 reduced
infarct volume by 65.6% (p = 0.0001), improved
weight loss (p < 0.05), and improved functional outcome measures (p < 0.05) when compared to PBS controls, improvements which were generally greater in magnitude than those observed for 2 mg/kg of rhPDV. In addition, treatment with 6 mg/kg of rhPDVLG3 was observed to significantly reduce mortality due to
stroke in one model, an outcome not previously observed for rhPDV. Our initial findings suggest that treatment with rhPDVLG3 provides significant improvement in neuroprotective and functional outcomes in experimental
stroke models and that further investigation of rhPDVLG3 as a novel neuroprotective
therapy for patients with
stroke is warranted.