Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 93, Issue -, Pages 288-298Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2020.12.027
Keywords
Agaphelin; Neutrophil elastase inhibitor; Experimental stroke; Thromboinflammation; Inflammation; Thrombosis; Antithrombotic; Bleeding complication; Blood-brainbarrier; Apoptosis
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB 688, TP A13]
- DFG [428778684]
- NIAID/NIH [Z01 AI000810-20]
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Recent research has shown that agaphelin has multiple antithrombotic effects and is protective in ischemic stroke. This protection is characterized by smaller infarct volume, reduced neurological deficits, and decreased animal mortality. Importantly, the protective effect of agaphelin does not increase the risk of intracerebral bleeding.
Recently it was shown that the hematophagous salivary gland protein agaphelin exhibits multiple antithrombotic effects without promoting the risk of bleeding. Agaphelin inhibits neutrophil elastase and thereby reduces cathepsin G-induced platelet aggregation. However, it is still unclear, whether pharmacological treatment with agaphelin in brain ischemia is protective and, regarding its bleeding risk, safe. To elucidate this issue, male C57BL/6 mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) and treated with 0.25 mg/kg agaphelin intravenously immediately after tMCAO. On day 1 and 7, infarct volume and functional neurological outcome were assessed by behavioural tests, histochemistry and magnetic resonance imaging. Thrombus formation, intracerebral bleeding risk, blood-brain barrier damage and the local inflammatory response were determined on day 1. This study shows for the first time a protective effect of agaphelin characterized by smaller infarct volume, reduced neurological deficits and reduced animal mortality. This protective effect was associated with reduced local thrombus formation, increased blood-brain barrier integrity and reduced brain inflammatory response. It is essential to mention that the protective effect of agaphelin was not linked to an increased risk of intracerebral bleeding. The promotion of brain tissue survival and inhibition of thromboinflammation identifies agaphelin as a promising treatment option in ischemic stroke, which considering the lack of bleeding risk should potentially be safe.
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