Intranasal delivery of cell-penetrating anti-NF-κB peptides (Tat-NBD) alleviates infection-sensitized hypoxic-ischemic brain injury.
Perinatal infection aggravates neonatal hypoxic-ischemic (HI) brain injury and may interfere with therapeutic hypothermia. While the NF-κB signaling pathway has been implicated in microglia activation in infection-sensitized HI, the current therapeutic strategies rely on systemic intervention, which could impair neonatal immunity and increase the risk of severe infection. To devise a brain-targeted anti-NF-κB strategy, we examined the effects of intranasal delivery of tat-NBD peptides in two animal models of neonatal infection-sensitized HI. Kinetic experiments showed that tat-NBD peptides entered the olfactory bulbs rapidly (10-30 min) and peaked in the cerebral cortex around 60 min after intranasal application in P7 rats. Further, intranasal delivery of 1.4 mg/kg tat-NBD, which is only 7% of the intravenous dose in past studies, markedly attenuated NF-κB signaling, microglia activation, and brain damage triggered by HI with 4 or 72 h pre-exposure to the bacterial endotoxin lipopolysaccharide (LPS). In contrast, intranasal delivery of mutant tat-NBD peptides or systemic application of minocycline failed to block LPS-sensitized HI injury. Yet, intranasal delivery of up to 5.6 mg/kg tat-NBD peptides immediately after pure-HI insult showed little protection, likely due to its rapid clearance from the brain and inability to inhibit parenchymal plasminogen activators. Together, these results suggest a novel therapy of infection-sensitized HI brain injury in newborns.
Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Dianer
D
Yang
Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Yu-Yo
YY
Sun
Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Xiaoyi
X
Lin
Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Jessica M
JM
Baumann
Imaging Research Center, Department of Radiology, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
R Scott
RS
Dunn
Imaging Research Center, Department of Radiology, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Diana M
DM
Lindquist
Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center, Cincinnati, OH 45229.
Chia-Yi
CY
Kuan
D000281:Administration, Intranasal; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D013778:Tetrazolium Salts
C100745:Aif1 protein, rat; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; C520609:Ikbkg protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D016328:NF-kappa B; D010455:Peptides; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
Hypoxia–ischemia; Microglia; NF-kB; Neuroinflammation