A decoy oligonucleotide inhibiting nuclear factor-kappaB binding to the IgGkappaB consensus site reduces cerebral injury and apoptosis in neonatal hypoxic-ischemic encephalopathy.
We examined the effect of treatment with intraventricular injection of a decoy oligonucleotide that binds and inhibits nuclear factor-kappaB on cytokine expression, ICAM-1 expression, neutrophil recruitment, apoptosis, and tissue injury in a model of neonatal hypoxic-ischemic cerebral injury with varying degrees of hypoxia. We found a reduction of interleukin-1beta, tumor necrosis factor-alpha, soluble ICAM-1, neutrophil counts, and activity after 2 hr of hypoxia, but not with 90 min of hypoxia. By contrast, a significant reduction of apoptosis was seen in animals treated after 90 min of hypoxia but not in those treated after 2 hr of hypoxia. Overall evidence of an inflammatory response was sparse, with low levels of ICAM-1 expression and neutrophil recruitment even in the more severe hypoxic ischemic injury. It is likely that the decoy oligonucleotide affects cerebral injury and apoptosis not through suppression of downstream elements of the inflammatory response but through other mechanisms, one of which is the reduction of transcription and synthesis of cytokines, which are known to affect other responses to cellular injury.
Fabian
Roderic H
RH
Department of Neurology of the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center, Houston, Texas 77030, USA. rfabian@bcm.tmc.edu
Perez-Polo
J Regino
JR
Kent
Thomas A
TA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016384:Consensus Sequence / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D007276:Injections, Intraventricular; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D009841:Oligonucleotides / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007074:Immunoglobulin G; D053583:Interleukin-1beta; D016328:NF-kappa B; D009841:Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1