Calpain inhibitor MDL-28170 reduces the functional and structural deterioration of corpus callosum following fluid percussion injury

J Neurotrauma. 2007 Jun;24(6):960-78. doi: 10.1089/neu.2006.0224.

Abstract

It is known that calpain activation is involved in human traumatic brain injury (TBI) and that calpain inhibition can have neuroprotective effects on both gray matter and white matter injury of TBI models. However, the role of calpain activation in the corpus callosum remains unclear and requires elucidation given its potential clinical relevance. We evaluated the neuroprotective effects of calpain inhibitor MDL-28170 on corpus callosum function and structural destruction using a fluid percussion injury (FPI) model. The therapeutic time window for a single administration of MDL-28170 was up to 4 h post injury in protecting the corpus callosum structural integrity, and up to 30 min in protecting the axonal function evaluated 1 day following injury. When given 30 min prior injury, MDL-28170 showed neuroprotective effects that lasted up to 7 days. However, 30 min post injury administration of the drug afforded neuroprotection only up to 3 days. In contrast, two additional reinforcement injections at 24 and 48 h in addition to 30 min post FPI significantly protected both axonal function and structural integrity that lasted 14 days following FPI. Our data indicated that calpain inhibitor MDL-28170 is an effective neuroprotectant for axonal injury in corpus callosum following FPI with a therapeutic time window up to 4 hours. Although delayed treatment (2 or 4 h post FPI) was effective in protecting the axonal structure, the axons saved may not be as functional as normal fibers. Multiple drug administrations may be necessary for achieving a persisting effectiveness of this compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • Axons / pathology
  • Brain Injuries / drug therapy*
  • Brain Injuries / metabolism
  • Brain Injuries / physiopathology
  • Calpain / antagonists & inhibitors*
  • Calpain / metabolism
  • Corpus Callosum / drug effects*
  • Corpus Callosum / pathology
  • Corpus Callosum / physiopathology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cysteine Proteinase Inhibitors / therapeutic use
  • Diffuse Axonal Injury / drug therapy*
  • Diffuse Axonal Injury / metabolism
  • Diffuse Axonal Injury / physiopathology
  • Dipeptides / pharmacology*
  • Dipeptides / therapeutic use
  • Disease Models, Animal
  • Drug Administration Schedule
  • Male
  • Neural Conduction / drug effects
  • Neural Conduction / physiology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Treatment Outcome
  • Wallerian Degeneration / drug therapy
  • Wallerian Degeneration / metabolism
  • Wallerian Degeneration / physiopathology

Substances

  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Neuroprotective Agents
  • Calpain
  • calpain inhibitor III