TY - JOUR
T1 - Elastase inhibitor agaphelin protects from acute ischemic stroke in mice by reducing thrombosis, blood–brain barrier damage, and inflammation
AU - Leinweber, Jonas
AU - Mizurini, Daniella M.
AU - Francischetti, Ivo M.B.
AU - Fleischer, Michael
AU - Hermann, Dirk M.
AU - Kleinschnitz, Christoph
AU - Langhauser, Friederike
N1 - Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): SFB 688, TP A13 to CK, DFG Projectnumber 428778684 (FOR-2879, TP A4 and B1 to FL, CK and DMH) and partially by NIAID/NIH grant # Z01 AI000810-20.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Agaphelin
KW - Antithrombotic
KW - Apoptosis
KW - Bleeding complication
KW - Blood-brainbarrier
KW - Experimental stroke
KW - Inflammation
KW - Neutrophil elastase inhibitor
KW - Thromboinflammation
KW - Thrombosis
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U2 - 10.1016/j.bbi.2020.12.027
DO - 10.1016/j.bbi.2020.12.027
M3 - Article
C2 - 33401017
AN - SCOPUS:85099615145
SN - 0889-1591
VL - 93
SP - 288
EP - 298
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -