Innate defense regulator peptide 1018 protects against perinatal brain injury.

Abstract

OBJECTIVE:

There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury; therefore, the neuroprotective therapeutic potential of innate defense regulator peptides (IDRs) was investigated.

METHODS:

The anti-inflammatory effects of 3 IDRs was measured in lipopolysaccharide (LPS)-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3 hours after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 hours before LPS or 3 hours after LPS+HI.

RESULTS:

IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3 hours after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for, eg, Fadd and Tnfsf9) and inflammatory (for, eg, interleukin 1, tumor necrosis factor α, chemokines, and cell adhesion molecules) pathways and showed marked protection of both white and gray brain matter.

INTERPRETATION:

IDR-1018 suppresses proinflammatory mediators and cell injurious mechanisms in the developing brain, and postinsult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both gray and white matter, and lacks significant effects on the brain under normal conditions. Thus, this peptide provides the features of a promising neuroprotective agent in newborns with brain injury.

• Authors: Hayde Bolouri, Karin Sävman, Wei Wang, Anitha Thomas, Norbert Maurer, Edie Dullaghan, Christopher D Fjell, C Joakim Ek, Henrik Hagberg, Robert E W Hancock, Kelly L Brown, Carina Mallard
• Journal: Annals of neurology (Ann Neurol) Vol. 75 Issue 3 Pg. 395-410 (Mar 2014) ISSN: 1531-8249 [Electronic] United States
• PMID: 24339166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Child Neurology Society/American Neurological Association.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antimicrobial Cationic Peptides
• Inflammation Mediators
• Lipopolysaccharides
• Neuroprotective Agents
• innate defense regulating peptide 1018

Topics

• Animals
• Animals, Newborn
• Anti-Inflammatory Agents, Non-Steroidal (metabolism, therapeutic use)
• Antimicrobial Cationic Peptides (metabolism, pharmacokinetics, therapeutic use)
• Apoptosis (drug effects)
• Brain Injuries (metabolism)
• Cerebral Cortex (metabolism)
• Female
• Gene Expression Regulation, Developmental (drug effects)
• Hypoxia-Ischemia, Brain (drug therapy, metabolism)
• Inflammation (drug therapy)
• Inflammation Mediators (metabolism)
• Lipopolysaccharides
• Male
• Mice
• Microglia (drug effects, metabolism)
• Nerve Fibers, Myelinated (drug effects)
• Nerve Fibers, Unmyelinated (drug effects)
• Neuroprotective Agents (metabolism, pharmacokinetics, therapeutic use)
• Primary Cell Culture
• Tissue Distribution