A comparison of YM-14673, U-50488H, and nalmefene after spinal cord injury in the rat.
A reproducible spinal cord injury model was used to compare the efficacy of three compounds previously shown to improve neurologic recovery after injury in rats: The thyrotropin releasing hormone (TRH) analogue, YM-14673; the specific kappa-opioid agonist, U-50488H; and the opioid antagonist, nalmefene, which has increased activity at kappa-receptors. A moderate injury in rats that results in recovery of uncoordinated gross locomotion was made at spinal T9 by rapid displacement (1.1. mm) of the cord. Compounds (or vehicle) were given either by intravenous bolus or by continuous mini-osmotic pump over 7 days, beginning 30 min after the injury as follows: controls (saline), YM-14673 (1 mg/kg bolus), U-50488H (10 mg/kg bolus), U-50488H (0.425 mg/kg/h continuous infusion x 7 days); nalmefene (0.1 mg/kg bolus); and nalmefene (0.021 mg/kg/h continuous infusion x 7 days). Neurologic recovery was assessed for 4 weeks by open-field walking, inclined plane, grid walking, and footprint analysis. The percentage of white matter spared was determined at the lesion epicenter. Only those groups given a bolus of YM14673, U-50488H, and nalmefene had open-field performance better than the scores of controls. Animals that received a bolus of YM-14673 also scored better than controls on the inclined plane and were more likely than controls to recover sufficiently to be tested by both grid walking and footprint analysis. Improved behavioral recovery was not found in groups that received chronic drug infusion. Histology demonstrated significant sparing of white matter for the YM-14673-treated group compared with controls; groups given a U-50488H and nalmefene bolus showed a trend for greater sparing of white matter. The results confirm a beneficial effect for these compounds and suggest that they may be useful in treatment of clinical spinal cord injury.
Behrmann
D L
DL
Division of Neurological Surgery, Ohio State University, Columbus 43210.
Bresnahan
J C
JC
Beattie
M S
MS
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009420:Nervous System / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*
D001384:Azetidines; D004151:Dipeptides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C054995:azetirelin; C038981:nalmefene