title: Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection.
abstract: Cervical spinal cord injury (SCI) can result in devastating functional deficits that involve the respiratory and hand function. The mammalian spinal cord has limited ability to regenerate and restore meaningful functional recovery following SCI. Riluzole, 2-amino-6-trifluoromethoxybenzothiazole, an anti-glutamatergic drug has been shown to reduce excitotoxicity and confer neuroprotection at the site of injury following experimental SCI. Based on promising preclinical studies, riluzole is currently under Phase III clinical trial for the treatment of SCI (ClinicalTrials.gov: NCT01597518). Riluzole's anti-glutamatergic role has the potential to regulate neuronal function and provide neuroprotection and influence glutamatergic connections distal to the initial injury leading to enhanced functional recovery following SCI. In order to investigate this novel role of riluzole we used a high cervical hemisection model of SCI, which interrupts all descending input to motoneurons innervating the ipsilateral forelimb and diaphragm muscles. Following C2 spinal cord hemisection, animals were placed into one of two groups: one group received riluzole (8 mg/kg) 1 h after injury and every 12 h thereafter for 7 days at 6 mg/kg, while the second group of injured rats received vehicle solution for the same duration of time. A third group of sham injured rats underwent a C2 laminectomy without hemisection and served as uninjured control rats. Interestingly, this study reports a significant loss of motoneurons within the cervical spinal cord caudal to C2 hemisection injury. Disruption of descending input led to a decrease in glutamatergic synapses and motoneurons caudal to the injury while riluzole treatment significantly limited this decline. Functionally, Hoffmann reflex recordings revealed an increase in the excitability of the remaining ipsilateral cervical motoneurons and significant improvements in skilled and unskilled forelimb function and respiratory motor function in the riluzole-treated animals. In conclusion, using a C2 hemisection injury model, this study provides novel evidence of motoneuron loss caudal to the injury and supports riluzole's capacity to promote neuronal preservation and function of neural network caudal to the SCI resulting in early and sustained functional improvements.
authors.affiliation: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Satkunendrarajah
authors.affiliation: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Nassiri
authors.affiliation: Department of Surgery, University of Toronto, Ontario, Canada.
authors.forename: S K
authors.initials: SK
authors.lastname: Karadimas
authors.affiliation: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Lip
authors.affiliation: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Yao
authors.affiliation: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Ontario, Canada. Electronic address: michael.fehlings@uhn.ca.
authors.forename: M G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D066193:Cervical Cord; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D015656:Respiratory Mechanics / Q000187:drug effects* / Q000502:physiology; D019782:Riluzole / Q000494:pharmacology / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D019782:Riluzole
keywords: Cervical spinal cord injury; Functional outcomes; Neuroprotection; Riluzole