Journal Article

FZJ-2023-02157

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity

Stokowska, A. ; Aswendt, M.FZJ* ; Zucha, D. ; Lohmann, S. ; Wieters, F. ; Morán Suarez, J. ; Atkins, A. L. ; Li, Y. ; Miteva, M. ; Lewin, J. ; Wiedermann, D. ; Diedenhofen, M. ; Torinsson Naluai, Å. ; Abaffy, P. ; Valihrach, L. ; Kubista, M. ; Hoehn, M.FZJ* ; Pekny, M. ; Pekna, M. (Corresponding author)

2023
ASCJ Ann Arbor, Mich.

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Please use a persistent id in citations: http://hdl.handle.net/2128/34466  doi:10.1172/JCI162253

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.

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Contributing Institute(s):

1. Kognitive Neurowissenschaften (INM-3)

Research Program(s):

1. 5251 - Multilevel Brain Organization and Variability (POF4-525) (POF4-525)
2. DFG project 431549029 - SFB 1451: Schlüsselmechanismen normaler und krankheitsbedingt gestörter motorischer Kontrolle (431549029) (431549029)

Appears in the scientific report 2023

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