Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity

0572871 - BTÚ 2024 RIV US eng J - Článek v odborném periodiku
Stokowska, A. - Aswendt, M. - Žucha, Daniel - Lohmann, S. - Wieters, F. - Suarez, J. M. - Atkins, Alison L. - Li, Y. - Miteva, M. - Lewin, J. - Wiedermann, D. - Diedenhofen, M. - Naluai, A. T. - Abaffy, Pavel - Valihrach, Lukáš - Kubista, Mikael - Hoehn, M. - Pěkný, M. - Pekna, M.
Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.
Journal of Clinical Investigation. Roč. 133, č. 10 (2023), č. článku 162253. ISSN 0021-9738. E-ISSN 1558-8238
Grant CEP: GA ČR(CZ) GA23-05327S
Institucionální podpora: RVO:86652036
Klíčová slova: FOCAL CEREBRAL-ISCHEMIA * SPINAL SENSITIZATION * CORTICOSPINAL TRACT
Obor OECD: Pathology
Impakt faktor: 15.9, rok: 2022
Způsob publikování: Open access
https://www.jci.org/articles/view/162253

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.
Trvalý link: https://hdl.handle.net/11104/0343552