title: Combinatorial treatment of acute spinal cord injury with ghrelin, ibuprofen, C16, and ketogenic diet does not result in improved histologic or functional outcome.
abstract: Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8-10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI.
authors.affiliation: International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Streijger
authors.forename: J H T
authors.initials: JH
authors.lastname: Lee
authors.forename: G J
authors.initials: GJ
authors.lastname: Duncan
authors.forename: M T L
authors.initials: MT
authors.lastname: Ng
authors.forename: P
authors.initials: P
authors.lastname: Assinck
authors.forename: T
authors.initials: T
authors.lastname: Bhatnagar
authors.forename: W T
authors.initials: WT
authors.lastname: Plunet
authors.forename: W
authors.initials: W
authors.lastname: Tetzlaff
authors.forename: B K
authors.initials: BK
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001557:Benzenesulfonates; D001696:Biomechanical Phenomena; D003183:Complement C6 / Q000627:therapeutic use*; D055423:Diet, Ketogenic / Q000379:methods*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D054439:Ghrelin / Q000627:therapeutic use*; D007052:Ibuprofen / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000178:diet therapy* / Q000188:drug therapy* / Q000503:physiopathology; D018709:Statistics, Nonparametric
chemical_list: D001557:Benzenesulfonates; D003183:Complement C6; D054439:Ghrelin; C010332:solochrome cyanine R; D007052:Ibuprofen
keywords: cervical SCI; combinatorial treatment; mechanism of action; spinal cord injury; time window