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Neuroimmunophilin ligand V-10,367 is neuroprotective after 24-hour delayed administration in a mouse model of diffuse traumatic brain injury.

Abstract
The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppressive neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg x 2 per day, by mouth) on neurofilament M (NFM) protein levels and on alpha-spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TBI mice treated with V-10,367 demonstrated significantly less neurodegeneration compared to injured, vehicle-treated mice. In summary, these results suggest that NIMMs may be neuroprotective indirectly through inhibition of calpain-mediated cytoskeletal damage and perhaps via maintenance of neuronal plasticity. In the context of this mouse model of TBI, the therapeutic window for V-10,367's positive effects is at least 24 hours after injury, which, in the case of TBI models, is largely unprecedented for a neuroprotective compound.
AuthorsNancy C Kupina, Megan R Detloff, Satavisha Dutta, Edward D Hall
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 22 Issue 10 Pg. 1212-21 (Oct 2002) ISSN: 0271-678X [Print] United States
PMID12368660 (Publication Type: Journal Article)
Chemical References
  • Ligands
  • Neurofilament Proteins
  • Neuroprotective Agents
  • Pyridines
  • V 10367
  • Spectrin
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Topics
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Administration, Oral
  • Animals
  • Body Weight (drug effects)
  • Brain Injuries (drug therapy)
  • Cerebral Cortex (drug effects, metabolism)
  • Corpus Striatum (drug effects, metabolism)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Hippocampus (drug effects, metabolism)
  • Ligands
  • Mice
  • Neurofilament Proteins (drug effects, metabolism)
  • Neuroprotective Agents (therapeutic use)
  • Parkinsonian Disorders (chemically induced, drug therapy)
  • Pyridines (therapeutic use)
  • Spectrin (metabolism)
  • Time Factors

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