title: Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic-ischemic brain injury.
abstract: Perinatal asphyxia-induced brain injury is often associated with irreversible neurological complications such as intellectual disability and cerebral palsy but available therapies are limited. Novel neuroprotective therapies as well as approaches stimulating neural plasticity mechanism that can compensate for cell death after hypoxia-ischemia (HI) are urgently needed. We previously reported that single i.c.v. injection of complement-derived peptide C3a 1h after HI induction prevented HI-induced cognitive impairment when mice were tested as adults. Here, we tested the effects of intranasal treatment with C3a on HI-induced cognitive deficit. Using the object recognition test, we found that intranasal C3a treated mice were protected from HI-induced impairment of memory function assessed 6weeks after HI induction. C3a treatment ameliorated HI-induced reactive gliosis in the hippocampus, while it did not affect the extent of hippocampal tissue loss, neuronal cell density, expression of the pan-synaptic marker synapsin I or the expression of growth associated protein 43. In conclusion, our results reveal that brief pharmacological treatment with C3a using a clinically feasible non-invasive mode of administration ameliorates HI-induced cognitive impairment. Intranasal administration is a plausible route to deliver C3a into the brain of asphyxiated infants at high risk of developing hypoxic-ischemic encephalopathy.
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: Anna
authors.initials: A
authors.lastname: Stokowska
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia.
authors.forename: Frederik R
authors.initials: FR
authors.lastname: Walker
authors.affiliation: Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.affiliation: Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Centre for the Developing Brain, King's College, London, UK; Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
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; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia. Electronic address: Marcela.Pekna@neuro.gu.se.
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology*; D015926:Complement C3a / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D019922:GAP-43 Protein / Q000096:biosynthesis / Q000235:genetics; D005911:Gliosis / Q000517:prevention & control; D006624:Hippocampus / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D021641:Recognition, Psychology / Q000187:drug effects; D016704:Synapsins / Q000096:biosynthesis
chemical_list: D019922:GAP-43 Protein; D018696:Neuroprotective Agents; D016704:Synapsins; D015926:Complement C3a
keywords: Behavioral deficit; Complement system; Hypoxia–ischemia; Neonatal encephalopathy; Reactive gliosis