title: Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia.
abstract: Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild-type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri-infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post-ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury.
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Stokowska
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Atkins
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Morán
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tulen
authors.initials: T
authors.lastname: Pekny
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Bulmer
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Michaela C
authors.initials: MC
authors.lastname: Pascoe
authors.affiliation: Department of Microbiology, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Barnum
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston, Houston, Texas, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
authors.affiliation: Department of Pharmacology and Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Marcela.Pekna@neuro.gu.se.|Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D015926:Complement C3a / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000187:drug effects / Q000235:genetics; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; D016704:Synapsins; D050598:Vesicular Glutamate Transport Protein 1; D015926:Complement C3a
keywords: complement; intranasal treatment; mice; recovery; stroke