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001007674 1001_ $$0P:(DE-HGF)0$$aStokowska, Anna$$b0
001007674 245__ $$aComplement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
001007674 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2023
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001007674 520__ $$aDespite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR–/–) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR–/– mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.
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001007674 7001_ $$0P:(DE-Juel1)196051$$aAswendt, Markus$$b1
001007674 7001_ $$00000-0002-2469-1315$$aZucha, Daniel$$b2
001007674 7001_ $$0P:(DE-HGF)0$$aLohmann, Stephanie$$b3
001007674 7001_ $$0P:(DE-HGF)0$$aWieters, Frederique$$b4
001007674 7001_ $$0P:(DE-HGF)0$$aMorán Suarez, Javier$$b5
001007674 7001_ $$aAtkins, Alison L.$$b6
001007674 7001_ $$aLi, YiXian$$b7
001007674 7001_ $$aMiteva, Maria$$b8
001007674 7001_ $$aLewin, Julia$$b9
001007674 7001_ $$aWiedermann, Dirk$$b10
001007674 7001_ $$aDiedenhofen, Michael$$b11
001007674 7001_ $$aTorinsson Naluai, Åsa$$b12
001007674 7001_ $$00000-0002-7571-8880$$aAbaffy, Pavel$$b13
001007674 7001_ $$00000-0002-6704-4337$$aValihrach, Lukas$$b14
001007674 7001_ $$aKubista, Mikael$$b15
001007674 7001_ $$0P:(DE-Juel1)176651$$aHoehn, Mathias$$b16
001007674 7001_ $$0P:(DE-HGF)0$$aPekny, Milos$$b17
001007674 7001_ $$00000-0003-2734-8237$$aPekna, Marcela$$b18$$eCorresponding author
001007674 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI162253$$gVol. 133, no. 10, p. e162253$$n10$$pe162253$$tThe journal of clinical investigation$$v133$$x0021-9738$$y2023
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