title: Activating Endogenous Neural Precursor Cells Using Metformin Leads to Neural Repair and Functional Recovery in a Model of Childhood Brain Injury.
abstract: The development of cell replacement strategies to repair the injured brain has gained considerable attention, with a particular interest in mobilizing endogenous neural stem and progenitor cells (known as neural precursor cells [NPCs]) to promote brain repair. Recent work demonstrated metformin, a drug used to manage type II diabetes, promotes neurogenesis. We sought to determine its role in neural repair following brain injury. We find that metformin administration activates endogenous NPCs, expanding the size of the NPC pool and promoting NPC migration and differentiation in the injured neonatal brain in a hypoxia-ischemia (H/I) injury model. Importantly, metformin treatment following H/I restores sensory-motor function. Lineage tracking reveals that metformin treatment following H/I causes an increase in the absolute number of subependyma-derived NPCs relative to untreated H/I controls in areas associated with sensory-motor function. Hence, activation of endogenous NPCs is a promising target for therapeutic intervention in childhood brain injury models.
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Parvati
authors.initials: P
authors.lastname: Dadwal
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Surgery, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Neemat
authors.initials: N
authors.lastname: Mahmud
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Laleh
authors.initials: L
authors.lastname: Sinai
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Azimi
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fatt
authors.affiliation: Department of Medicine, Pediatrics and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Surgery, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Institute of Biomaterial and Biomedical Engineering, University of Toronto, 563 Spadina Crescent, Toronto, ON M5S 2J7, Canada. Electronic address: cindi.morshead@utoronto.ca.
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D001930:Brain Injuries / Q000188:drug therapy*; D002465:Cell Movement; D002478:Cells, Cultured; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects; D055495:Neurogenesis; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D008687:Metformin