title: Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury.
abstract: Nerve injuries cause pain, paralysis and numbness that can lead to major disability, and newborns often sustain nerve injuries during delivery that result in lifelong impairment. Without a pharmacologic agent to enhance functional recovery from these injuries, clinicians rely solely on surgery and rehabilitation to treat patients. Unfortunately, patient outcomes remain poor despite application of the most advanced microsurgical and rehabilitative techniques. We hypothesized that the detrimental effects of traumatic neonatal nerve injury could be mitigated with pharmacologic neuroprotection, and tested whether the novel neuroprotective agent P7C3 would block peripheral neuron cell death and enhance functional recovery in a rat neonatal nerve injury model. Administration of P7C3 after sciatic nerve crush injury doubled motor and sensory neuron survival, and also promoted axon regeneration in a dose-dependent manner. Treatment with P7C3 also enhanced behavioral and muscle functional recovery, and reversed pathological mobilization of spinal microglia after injury. Our findings suggest that the P7C3 family of neuroprotective compounds may provide a basis for the development of a new neuroprotective drug to enhance recovery following peripheral nerve injury.
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada. Electronic address: stevekemp.phd@gmail.com.
authors.forename: S W P
authors.initials: SWP
authors.lastname: Kemp
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Szynkaruk
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: K N
authors.initials: KN
authors.lastname: Stanoulis
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: E H
authors.initials: EH
authors.lastname: Liu
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
authors.forename: M P
authors.initials: MP
authors.lastname: Willand
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Morlock
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Mangano
authors.affiliation: The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Beggs
authors.affiliation: The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
authors.forename: M W
authors.initials: MW
authors.lastname: Salter
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Gordon
authors.affiliation: Departments of Psychiatry, Neurology and Veterans Affairs, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: andrew-pieper@uiowa.edu.
authors.forename: A A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada; University of Toronto, Department of Surgery and Institute of Biomaterials and Biomedical Engineering, Toronto, ON, Canada. Electronic address: gregory.borschel@sickkids.ca.
authors.forename: G H
authors.initials: GH
authors.lastname: Borschel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002227:Carbazoles / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D059348:Peripheral Nerve Injuries / Q000150:complications*; D051381:Rats; D011917:Rats, Inbred Lew; D020426:Sciatic Neuropathy / Q000150:complications*; D012677:Sensation / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects; D013116:Spinal Cord / Q000473:pathology
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound
keywords: P7C3; functional recovery; microglia; neonatal nerve injury; neuroprotection