TY  - JOUR
AU  - Stokowska, Anna
AU  - Aswendt, Markus
AU  - Zucha, Daniel
AU  - Lohmann, Stephanie
AU  - Wieters, Frederique
AU  - Morán Suarez, Javier
AU  - Atkins, Alison L.
AU  - Li, YiXian
AU  - Miteva, Maria
AU  - Lewin, Julia
AU  - Wiedermann, Dirk
AU  - Diedenhofen, Michael
AU  - Torinsson Naluai, Åsa
AU  - Abaffy, Pavel
AU  - Valihrach, Lukas
AU  - Kubista, Mikael
AU  - Hoehn, Mathias
AU  - Pekny, Milos
AU  - Pekna, Marcela
TI  - Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
JO  - The journal of clinical investigation
VL  - 133
IS  - 10
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - FZJ-2023-02157
SP  - e162253
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 36995772
UR  - <Go to ISI:>//WOS:000998153000004
DO  - DOI:10.1172/JCI162253
UR  - https://juser.fz-juelich.de/record/1007674
ER  -