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@ARTICLE{Stokowska:1007674,
author = {Stokowska, Anna and Aswendt, Markus and Zucha, Daniel and
Lohmann, Stephanie and Wieters, Frederique and Morán
Suarez, Javier and Atkins, Alison L. and Li, YiXian and
Miteva, Maria and Lewin, Julia and Wiedermann, Dirk and
Diedenhofen, Michael and Torinsson Naluai, Åsa and Abaffy,
Pavel and Valihrach, Lukas and Kubista, Mikael and Hoehn,
Mathias and Pekny, Milos and Pekna, Marcela},
title = {{C}omplement {C}3a treatment accelerates recovery after
stroke via modulation of astrocyte reactivity and cortical
connectivity},
journal = {The journal of clinical investigation},
volume = {133},
number = {10},
issn = {0021-9738},
address = {Ann Arbor, Mich.},
publisher = {ASCJ},
reportid = {FZJ-2023-02157},
pages = {e162253},
year = {2023},
abstract = {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.},
cin = {INM-3},
ddc = {610},
cid = {I:(DE-Juel1)INM-3-20090406},
pnm = {5251 - Multilevel Brain Organization and Variability
(POF4-525) / DFG project 431549029 - SFB 1451:
Schlüsselmechanismen normaler und krankheitsbedingt
gestörter motorischer Kontrolle (431549029)},
pid = {G:(DE-HGF)POF4-5251 / G:(GEPRIS)431549029},
typ = {PUB:(DE-HGF)16},
pubmed = {36995772},
UT = {WOS:000998153000004},
doi = {10.1172/JCI162253},
url = {https://juser.fz-juelich.de/record/1007674},
}