Rt-PA did not elevate brain albumin and haemoglobin levels in sham mice or in mice subjected to 0.5 h MCAo. Albumin and haemoglobin content were measured in the perfused mouse brains 24 h post MCAo as indications of blood–brain barrier (BBB) compromise and HT, respectively. rt-PA (10 mg/kg) or its vehicle, with or without the LDL receptor antagonist, receptor-associated protein (RAP 2 mg/kg), were intravenously injected at reperfusion after 0.5 or 4 h of middle cerebral artery occlusion (MCAo). We aimed to simulate rt-PA-induced haemorrhagic transformation (HT) in a mouse model of stroke and to assess if it drives symptomatic neurological deterioration and whether it is attenuated by LDL receptor blockade. rt-PA also undermines cerebral vasculature stability in a multimodal process which involves engagement with LDL receptor-related protein 1 (LRP-1), potentially underlying the development of sICH. Symptomatic intracerebral haemorrhage (sICH) following tissue-type plasminogen activator (rt-PA) administration is the most feared and lethal complication of thrombolytic therapy for ischaemic stroke, creating a significant obstacle for a broader uptake of this beneficial treatment.
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