Key result
Depletion of platelet GPVI prior to stroke was safe and effective, even with rt-PA, whereas targeting integrin α2β1 did not reduce stroke size or improve functional outcome.
Why the study?
No preclinical stroke study had addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion injury.
Does targeting platelet GPVI or integrin α2β1 reduce ischemic brain damage in a mouse model of focal cerebral ischemia?
Does targeting platelet GPVI or integrin α2β1 reduce ischemic brain damage in a mouse model of focal cerebral ischemia?
In a mouse model of ischemic stroke, targeting platelet GPVI, but not integrin α2β1, safely and effectively reduced ischemic brain damage even with concurrent rt-PA administration.
Supports GPVI targeting in mouse stroke models even with rt-PA; leaves open human translation and α2β1 relevance.
Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2−/− mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.
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Schuhmann et al. (2019) studied Ischemic stroke. Anti-GPVI antibody (JAQ1) plus rt-PA or anti-integrin α2β1 (LEN/B) vs. Wild-type / untreated was evaluated on Stroke outcome (infarct size and neurological scoring). Depletion of platelet GPVI prior to stroke was safe and effective, even with rt-PA, whereas targeting integrin α2β1 did not reduce stroke size or improve functional outcome.
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