This title appears in the Scientific Report :
2023
Please use the identifier:
http://dx.doi.org/10.1172/JCI162253 in citations.
Please use the identifier: http://hdl.handle.net/2128/34466 in citations.
Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
Despite 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 neurodev...
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Personal Name(s): | Stokowska, Anna |
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Aswendt, Markus / Zucha, Daniel / Lohmann, Stephanie / Wieters, Frederique / Morán Suarez, Javier / Atkins, Alison L. / Li, YiXian / Miteva, Maria / Lewin, Julia / Wiedermann, Dirk / Diedenhofen, Michael / Torinsson Naluai, Åsa / Abaffy, Pavel / Valihrach, Lukas / Kubista, Mikael / Hoehn, Mathias / Pekny, Milos / Pekna, Marcela (Corresponding author) | |
Contributing Institute: |
Kognitive Neurowissenschaften; INM-3 |
Published in: | The journal of clinical investigation, 133 (2023) 10, S. e162253 |
Imprint: |
Ann Arbor, Mich.
ASCJ
2023
|
DOI: |
10.1172/JCI162253 |
Document Type: |
Journal Article |
Research Program: |
SFB 1451: Schlüsselmechanismen normaler und krankheitsbedingt gestörter motorischer Kontrolle Multilevel Brain Organization and Variability |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/34466 in citations.
Despite 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. |