The functional and neuroprotective actions of Neu2000, a dual-acting pharmacological agent, in the treatment of acute spinal cord injury.
The goal of the present study was to examine the neuroprotective and functional significance of targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress using a dual-acting compound, Neu2000, in rat model of moderate spinal cord injury (SCI). An initial set of experiments was conducted in uninjured rats to study the pharmacokinetic profile of Neu2000 following intraperitoneal and intravenous administration. A second experiment measured free radical production in mitochondria isolated from sham or injured spinal cords of animals receiving vehicle or Neu2000 treatment. A third set of animals was divided into three treatment groups consisting of vehicle treatment, a single dose of Neu2000 (50 mg/kg) administered at 10 min following injury, or a repeated treatment paradigm consisting of a single bolus of Neu2000 at 10 min following injury (50 mg/kg) plus a maintenance dose (25 mg/kg) administered every 24 h for an additional 6 days. Animals were tested once a week for a period of 6 weeks for evidence of locomotor recovery in an open field and kinematic analysis of fine motor control using the DigiGait Image Analysis System. At the end of the testing period, spinal cord reconstruction was performed to obtain nonbiased stereological measures of tissue sparing. The results of this study demonstrate that Neu2000 treatment significantly reduced the production of mitochondrial free radicals and improved locomotor outcomes that were associated with a significant increase in the volume of spared spinal cord tissue.
Springer
Joe E
JE
Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, Kentucky 40536-0509, USA. joe.springer@uky.edu
Rao
Ravikumar Rangaswamy
RR
Lim
Hyang Ran
HR
Cho
Sung Ig
SI
Moon
Gyoeng Joon
GJ
Lee
Hee Young
HY
Park
Eui Jin
EJ
Noh
Jai Sung
JS
Gwag
Byoung Joo
BJ
D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics / Q000627:therapeutic use; D001565:Benzoates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005464:Fluorobenzenes; D005609:Free Radicals / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012459:Salicylates; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D062368:meta-Aminobenzoates
C519903:2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid; D000975:Antioxidants; D001565:Benzoates; D005464:Fluorobenzenes; D005609:Free Radicals; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012459:Salicylates; D062368:meta-Aminobenzoates