title: Evaluation of the effects of riluzole on adult spinal cord-derived neural stem/progenitor cells in vitro and in vivo.
abstract: Riluzole, a sodium/glutamate antagonist, has shown significant neuroprotective effects in experimental models of spinal cord injury (SCI) and is currently under clinical trial for patients with SCI. However, the effect of riluzole on adult spinal cord-derived NSPCs remains unknown. In this study, we examined the effects of riluzole on NSPC survival both in vitro and in vivo. NSPCs harvested from the adult rat spinal cord were exposed to riluzole (1-30 μM) either alone or in combination with hydrogen peroxide or glutamate in vitro. Measures of intracellular reactive oxygen species (ROS), cell viability and proliferation were assessed. To examine the effects of riluzole on transplanted NSPCs in vivo, a rodent clip compression model of SCI was used. One week after injury, NSPCs were transplanted into the spinal cord and rats received either riluzole or vehicle treatment for two weeks (similar to the clinically accepted dosing regimen) at which time cords were processed for analysis. Exposure to riluzole (≥ 10 μM) for more than 48 h in vitro reduced NSPC viability. Riluzole treatment (1-10 μM) did not significantly affect intracellular ROS levels or cell viability in the setting of in vitro oxidative stress. While glutamate (500 μM) exposure for 96 h significantly increased adult NSPC proliferation and survival, this response was not blocked by concurrent treatment with riluzole (1-10 μM) thus supporting the notion that the known anti-glutamatergic properties of riluzole are not mediated through direct inhibition of glutamate receptors. Furthermore, riluzole treatment did not impair the survival of transplanted NSPCs in a rodent model of SCI. These results suggest that although NSPCs may have a narrow tolerance to riluzole treatment in vitro, riluzole does not impair NSPC survival at doses that would be used clinically.
authors.affiliation: Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, ON, Canada. Electronic address: laureen.hachem@mail.utoronto.ca.
authors.forename: Laureen D
authors.initials: LD
authors.lastname: Hachem
authors.affiliation: Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, ON, Canada. Electronic address: amothe@uhnres.utoronto.ca.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Mothe
authors.affiliation: Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, ON, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, ON, Canada. Electronic address: charles.tator@uhn.ca.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006836:Hydro-Lyases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D016877:Oxidants / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D019782:Riluzole; D006861:Hydrogen Peroxide; D006836:Hydro-Lyases; C045581:lactate dehydratase
keywords: Glutamate; Neural stem cells; Oxidative stress; Riluzole; Spinal cord injury