Inhibition of Myosin light-chain kinase attenuates cerebral edema after traumatic brain injury in postnatal mice.

Abstract

Traumatic brain injury (TBI) in children less than 8 years of age leads to decline in intelligence and executive functioning. Neurological outcomes after TBI correlate to development of cerebral edema, which affect survival rates after TBI. It has been shown that myosin light-chain kinase (MLCK) increases cerebral edema and that pretreatment with an MLCK inhibitor (ML-7) reduces cerebral edema. The aim of this study was to determine whether inhibition of MLCK after TBI in postnatal day 24 (PND-24) mice would prevent breakdown of the blood-brain barrier (BBB) and development of cerebral edema and improve neurological outcome. We used a closed head injury model of TBI. ML-7 or saline treatment was administered at 4 h and every 24 h until sacrifice or 5 days after TBI. Mice were sacrificed at 24 h, 48 h, and 72 h and 7 days after impact. Mice treated with ML-7 after TBI had decreased levels of MLCK-expressing cells (20.7±4.8 vs. 149.3±40.6), less albumin extravasation (28.3±11.2 vs. 116.2±60.7 mm(2)) into surrounding parenchymal tissue, less Evans Blue extravasation (339±314 vs. 4017±560 ng/g), and showed a significant difference in wet/dry weight ratio (1.9±0.07 vs. 2.2±0.05 g), compared to saline-treated groups. Treatment with ML-7 also resulted in preserved neurological function measured by the wire hang test (57 vs. 21 sec) and two-object novel recognition test (old vs. new, 10.5 touches). We concluded that inhibition of MLCK reduces cerebral edema and preserves neurological function in PND-24 mice.

• Authors: Janet L Rossi, Tracey Todd, Nicolas G Bazan, Ludmila Belayev
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 30 Issue 19 Pg. 1672-9 (Oct 01 2013) ISSN: 1557-9042 [Electronic] United States
• PMID: 23984869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Albumins
• Azepines
• Coloring Agents
• Enzyme Inhibitors
• Naphthalenes
• ML 7
• Evans Blue
• Myosin-Light-Chain Kinase

Topics

• Albumins (biosynthesis)
• Animals
• Azepines (therapeutic use)
• Behavior, Animal (drug effects)
• Blood-Brain Barrier (drug effects)
• Brain Edema (drug therapy, pathology)
• Brain Injuries (drug therapy, pathology, psychology)
• Coloring Agents
• Enzyme Inhibitors (therapeutic use)
• Evans Blue
• Male
• Mice
• Mice, Inbred C57BL
• Myosin-Light-Chain Kinase (antagonists & inhibitors, biosynthesis)
• Naphthalenes (therapeutic use)
• Psychomotor Performance (drug effects)
• Recognition, Psychology (drug effects)