Innate defense regulator peptide 1018 protects against perinatal brain injury
Hayde Bolouri1, Karin Sävman, Wei Wang
1Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Insights
Innate defense regulator peptides (IDRs) show promise for treating neonatal brain injury. IDR-1018 effectively reduced inflammation and protected brain matter after injury in preclinical models.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Perinatal brain injury is a significant concern with no current pharmacological treatments.
- Innate immune response activation is a key factor in perinatal brain injury.
Purpose of the Study:
- To investigate the neuroprotective potential of innate defense regulator peptides (IDRs).
- To assess IDR-1018's efficacy in a neonatal brain injury model.
Main Methods:
- Tested anti-inflammatory effects of 3 IDRs on lipopolysaccharide (LPS)-activated microglia in vitro.
- Evaluated IDR-1018 neuroprotection in vivo using a neonatal hypoxia-ischemia (HI) and LPS model.
- Analyzed gene expression patterns to understand peptide-mediated effects.
Main Results:
- IDR-1018 reduced inflammatory mediators in vitro and modulated neuroinflammation in vivo.
- Post-insult administration of IDR-1018 protected both white and gray brain matter.
- IDR-1018 affected apoptotic and inflammatory pathways.
Conclusions:
- IDR-1018 suppresses inflammation and protects against cell injury in the developing brain.
- Systemic IDR-1018 treatment is effective post-insult, conferring neuroprotection without adverse effects under normal conditions.
- IDR-1018 is a promising neuroprotective agent for neonatal brain injury.
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.
