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Nuclear factor-kappa B decoy attenuates neuronal damage after global brain ischemia: a future strategy for brain
T Ueno1, Y Sawa, S Kitagawa-Sakakida
1Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Objectives:
Recent studies have reported that cis element decoy oligodeoxynucleotides against nuclear factor-kappa B block the activation of genes that mediate ischemic injury. To improve brain protection during circulatory arrest in cardiac surgery, we evaluated the efficacy of nuclear factor-kappa B decoy oligodeoxynucleotides in preventing neuronal damage after global brain ischemia.
Methods:
Hemagglutinating virus of Japan-liposome complex with fluorescein isothiocyanate-labeled nuclear factor-kappa B decoy oligodeoxynucleotides was injected through the carotid artery during 20 minutes of global brain ischemia in rats to evaluate the efficacy of transfecting the decoy oligodeoxynucleotides. The messenger RNA levels of several factors related to ischemia-reperfusion injury in the hippocampus were estimated by a real-time polymerase chain reaction method 1 hour after reperfusion. Neuronal damage was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining and by using immunohistochemical study of microtubule-associated protein 2 in the hippocampus CA-1 region 7 days after ischemia.
Results:
Introduction of the nuclear factor-kappa B decoy oligodeoxynucleotides into rat brain neurons through the carotid artery during global brain ischemia was markedly successful. The polymerase chain reaction study showed that the transfected nuclear factor-kappa B decoy oligodeoxynucleotides effectively inhibited the expression of tumor necrosis factor alpha interleukin 1 beta and intracellular adhesion molecule 1 messenger RNA 1 hour after global brain ischemia. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining and microtubule-associated protein 2 immunohistochemistry showed that the transfected nuclear factor-kappa B decoy oligodeoxynucleotides significantly attenuated the neuronal damage 7 days after global brain ischemia.
Conclusions:
Therapeutic transfection of nuclear factor-kappa B decoy oligodeoxynucleotides during brain ischemia may be useful for attenuating neuronal damage, suggesting a strategy for cerebral protection against global ischemia.
Insights
Nuclear factor-kappa B decoy oligodeoxynucleotides successfully protected rat neurons from global brain ischemia. This approach significantly reduced inflammatory gene expression and neuronal damage, offering a promising strategy for cerebral protection.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Surgery
Background:
- Global brain ischemia during cardiac surgery leads to neuronal damage.
- Nuclear factor-kappa B (NF-κB) activation plays a key role in ischemia-reperfusion injury.
- Decoy oligodeoxynucleotides targeting NF-κB have shown potential in blocking injury-mediating genes.
Purpose of the Study:
- To evaluate the efficacy of NF-κB decoy oligodeoxynucleotides in preventing neuronal damage after global brain ischemia.
- To assess the therapeutic potential of NF-κB decoy oligodeoxynucleotides for cerebral protection during circulatory arrest.
Main Methods:
- Rats underwent 20 minutes of global brain ischemia with carotid artery injection of NF-κB decoy oligodeoxynucleotides complexed with hemagglutinating virus of Japan-liposome.
- Messenger RNA levels of tumor necrosis factor alpha, interleukin-1 beta, and intracellular adhesion molecule-1 were measured via real-time PCR 1 hour post-reperfusion.
- Neuronal damage was assessed 7 days post-ischemia using TUNL staining and microtubule-associated protein 2 immunohistochemistry.
Main Results:
- Successful transfection of NF-κB decoy oligodeoxynucleotides into rat brain neurons was achieved.
- Transfected NF-κB decoy oligodeoxynucleotides significantly inhibited the expression of key inflammatory mediators (TNF-α, IL-1β, ICAM-1) mRNA.
- Significant attenuation of neuronal damage in the hippocampus CA-1 region was observed 7 days after ischemia.
Conclusions:
- Therapeutic transfection of NF-κB decoy oligodeoxynucleotides during brain ischemia is effective in attenuating neuronal damage.
- This strategy holds promise for cerebral protection against global ischemia, particularly in contexts like cardiac surgery.