Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury

S W P Kemp; M Szynkaruk; K N Stanoulis; M D Wood; E H Liu; M P Willand; L Morlock; J Naidoo; N S Williams; J M Ready; T J Mangano; S Beggs; M W Salter; T Gordon; A A Pieper; G H Borschel

doi:10.1016/j.neuroscience.2014.10.005

Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury

Neuroscience. 2015 Jan 22:284:202-216. doi: 10.1016/j.neuroscience.2014.10.005. Epub 2014 Oct 13.

Authors

S W P Kemp¹, M Szynkaruk², K N Stanoulis², M D Wood³, E H Liu², M P Willand³, L Morlock⁴, J Naidoo⁴, N S Williams⁴, J M Ready⁴, T J Mangano⁵, S Beggs⁶, M W Salter⁶, T Gordon³, A A Pieper⁷, G H Borschel⁸

Affiliations

¹ 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.
² Department of Surgery, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada.
³ 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.
⁴ Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
⁵ Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ The Hospital for Sick Children Research Institute, Program in Neuroscience and Mental Health, Toronto, ON, Canada.
⁷ 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.
⁸ 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.

PMID: 25313000
DOI: 10.1016/j.neuroscience.2014.10.005

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.

Keywords: P7C3; functional recovery; microglia; neonatal nerve injury; neuroprotection.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Carbazoles / therapeutic use*
Cell Proliferation / drug effects
Cell Survival / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Ganglia, Spinal / pathology
Male
Microglia / drug effects
Motor Neurons / drug effects
Movement Disorders* / drug therapy
Movement Disorders* / etiology
Movement Disorders* / pathology
Muscle Strength / drug effects
Nerve Regeneration / drug effects
Neuroprotective Agents / therapeutic use*
Peripheral Nerve Injuries / complications*
Rats
Rats, Inbred Lew
Sciatic Neuropathy / complications*
Sensation / drug effects*
Sensory Receptor Cells / drug effects
Spinal Cord / pathology

Substances

Carbazoles
Neuroprotective Agents
P7C3 compound

Abstract

Publication types

MeSH terms

Substances

Grants and funding