TY  - JOUR
A1  - Bieber, Michael
A1  - Schuhmann, Michael K.
A1  - Bellut, Maximilian
A1  - Stegner, David
A1  - Heinze, Katrin G.
A1  - Pham, Mirko
A1  - Nieswandt, Bernhard
A1  - Stoll, Guido
T1  - Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion
T2  - International Journal of Molecular Sciences
N2  - During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte–platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα–von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia–reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke.
KW  - ischemic penumbra
KW  - Orai2
KW  - glycoprotein receptor Ibα
KW  - ischemic stroke
KW  - thrombo-inflammation
KW  - middle cerebral artery occlusion
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/28603
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-286038
SN  - 1422-0067
VL  - 23
IS  - 16
ER  -