Inhibition of Myosin Light Chain Kinase Reduces Brain Edema Formation After Traumatic Brain Injury

J Neurochem. 2010 Feb;112(4):1015-25. doi: 10.1111/j.1471-4159.2009.06514.x. Epub 2009 Nov 27.

Abstract

The role of the endothelial contractile apparatus in the process of brain edema formation after brain trauma is not characterized. Phosphorylation of myosin light chains by myosin light chain kinases (MLCK) activates endothelial contractile elements and results in a rearrangement of the cytoskeleton. This may enhance post-traumatic blood-brain barrier dysfunction. In order to investigate the role of the MLCK on brain edema formation and blood-brain barrier permeability after brain injury, mice were anesthetized and subjected to a controlled cortical impact (CCI). MLCK expression is significantly up-regulated after CCI with a maximum 12 h post-injury. Specific inhibition of MLCK by ML-7 resulted in a reduction of phosphorylation of myosin light chains and improved blood-brain-barrier integrity. Accordingly, ML-7 attenuated post-traumatic brain edema formation and intracranial hypertension 24 h after CCI. Prevention of brain edema formation did not translate into improved neurological outcome or reduced brain lesion. In conclusion, the results confirm that the endothelial contractile apparatus is activated by CCI and opens the endothelial barrier leading to vasogenic brain edema formation. Lack of neurological and histological improvement suggests that specific targeting of vasogenic brain edema at the endothelial level is not sufficient to limit secondary brain damage and has, therefore, to be combined with other potential neuroprotective strategies.

MeSH terms

  • Animals
  • Azepines / therapeutic use*
  • Blood-Brain Barrier / drug effects
  • Brain Edema / drug therapy*
  • Brain Edema / etiology
  • Brain Edema / metabolism*
  • Brain Edema / pathology
  • Brain Injuries / complications*
  • Constriction
  • Disease Models, Animal
  • Drug Administration Schedule
  • Enzyme Inhibitors / therapeutic use*
  • Evans Blue
  • Functional Laterality
  • Gene Expression Regulation / drug effects
  • Intracranial Pressure / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myosin Light Chains / genetics
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / genetics
  • Myosin-Light-Chain Kinase / metabolism*
  • Naphthalenes / therapeutic use*
  • Neurologic Examination / methods
  • Statistics, Nonparametric
  • Time Factors

Substances

  • Azepines
  • Enzyme Inhibitors
  • Myosin Light Chains
  • Naphthalenes
  • ML 7
  • Evans Blue
  • Myosin-Light-Chain Kinase