Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice

Michael K Schuhmann,Alexander M Kollikowski,Katrin G Heinze,Mirko Pham,Maximilian Franke,David Stegner,Guido Stoll,Bernhard Nieswandt,Michael Bieber

doi:10.1186/s12974-021-02095-1

Michael K Schuhmann, Alexander M Kollikowski + Show 7 more

Open Access

https://doi.org/10.1186/s12974-021-02095-1

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Abstract

BackgroundIn acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood.MethodsTo address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1−/− mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion.ResultsWe show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion.ConclusionsProgressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.

Highlights

In acute ischemic stroke, the therapeutic success of recanalization by thrombolysis and/or mechanical thrombectomy (MTE) largely depends on the extent of structural brain damage before the intervention [1] and on ischemia/ reperfusion (I/R) injury thereafter [2]
Based on findings in pathophysiological different ischemia/reperfusion paradigms of cerebral ischemia [2, 18, 19], we addressed the role of platelet glycoprotein Ib (GPIb) in conjunct with T-cells during MCA occlusion
Infarct volumes in mice treated with anti-GPIbFab were significantly reduced compared to control Fabtreated animals at the corresponding time points, as revealed by triphenyltetrazolium chloride (TTC) (Fig. 1a), Nissl (Fig. S1), and MAP2 stainings (2 h middle cerebral artery occlusion (MCAO): Ctrl Fab: Med. 27.2 (25%: 19.3; 75%: 38.5) mm3; anti-GPIb Fab: Med. 7.0 (25%: 5.2; 75%: 21.1) mm3, P < 0.05; 3 h MCAO: Ctrl Fab: Med. 58.5 (25%: 45.3; 75%: 70.9) mm3; anti-GPIb Fab: Med. 31.0 (25%: 16.1; 75%: 34.5) mm3, P < 0.05; 4 h MCAO: Ctrl Fab: Med. 66.1 (25%: 55.8; 75%: 74.2) mm3; anti-GPIb Fab: Med. 29.0 (25%: 0.0; 75%: 41.1) mm3, P < 0.001) (Fig. 1b)

Summary

Introduction

The therapeutic success of recanalization by thrombolysis and/or mechanical thrombectomy (MTE) largely depends on the extent of structural brain damage before the intervention [1] and on ischemia/ reperfusion (I/R) injury thereafter [2]. The survival of the ischemic penumbra, defined as dysfunctional, but still viable brain tissue under occlusion of a major cerebral artery, critically depends on residual collateral blood flow At present, it is unclear whether collateral blood flow exhausts primarily [9,10,11,12] or secondarily as a consequence of increased microvascular resistance which would physically impair perfusion pressure [13]. It has been demonstrated in experimental stroke models that the microcirculation is immediately affected during cerebral ischemia [14]. In hyperacute human stroke, leukocytes accumulate within the secluded vessel territory distal to MCA occlusion [17] At present, it is unclear, whether these platelet/leukocyte accumulations functionally contribute to primary infarct growth. The underlying mechanisms of progressive infarction are not fully understood

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