The Role of NF-κB Triggered Inflammation in Cerebral Ischemia

Abstract

Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death. However, there is presently a matter of controversy over whether inflammation could either be involved in brain damage or be a necessary part of brain repair. The inflammatory response is triggered by inflammasomes, key multiprotein complexes that promote secretion of pro-inflammatory cytokines. An early event in post-ischemic brain tissue is the release of certain molecules and reactive oxygen species (ROS) from injured neurons which induce the expression of the nuclear factor-kappaB (NF-κB), a transcription factor involved in the activation of the inflammasome. There are conflicting observations related to the role of NF-κB. While some observe that NF-κB plays a damaging role, others suggest it to be neuroprotective in the context of cerebral ischemia, indicating the need for additional investigation. Here we discuss the dual role of the major inflammatory signaling pathways and provide a review of the latest research aiming to clarify the relationship between NF-κB mediated inflammation and neuronal death in cerebral ischemia.

Protective Effect of Beta-Carotene against Myeloperoxidase- Mediated Oxidative Stress and Inflammation in Rat Ischemic Brain Injury

“…It is well recognized that the NF-κB transcription factor has a key function in regulation of inflammatory responses, immune functions, and cell survival by acting as a central mediator for induction of multiple pro-inflammatory genes [ 45 ]. Consequently, the deregulated activation of NF-κB signaling contributes to the pathogenesis of various inflammatory processes, including cerebral ischemic damage.…”

To study the mechanism of panax notoginseng in the treatment of aspirin resistance in the secondary prevention of stroke based on TLR4/MyD88/NF-κB signaling pathway: A study protocol

“…In addition, inflammatory factors and adhesion molecules can induce further NF- κ B activation and aggravate the inflammatory process. [ 25 ] Studies have shown that total saponins of Panax notoginseng (Sanqi ) can inhibit the NF- κ B activation, block the I κ B phosphorylation, reduce the NF- κ B transcription into the nucleus, inhibit the expression of TNF- α in ischemic brain tissue. [ 26 ] TLR4, a member of the signal transduction family, binded to the adaptor protein MyD88 and interleukin-related kinases to activate the TLR4/MyD88/NF- κ B signaling pathway could induce inflammatory responses.…”

NF-kB (p50/p65)-Mediated Pro-Inflammatory microRNA (miRNA) Signaling in Alzheimer's Disease (AD)

“…In general, therapeutic NF-kB inhibition can occur via four basic mechanistic strategies: (i) by blockage of the original physiological stimulating signals that drive NF-kB activation; (ii) by targeting phosphorylation pathways associated with NF-kB activation because NF-κB phosphorylation controls transcription in a gene-specific manner; (iii) by modulation or activation of the IkB complex or other NF-kB subunits; and/or (iv) by blockage of NF-kB translocation, DNA sequence recognition, and binding and/or modification of NF-kB that affects its activity or target specificity. These approaches include but are not limited to the following strategies, most of which are under very active research and therapeutic development: (i) antioxidant approaches that neutralize the primary NF-kB activation signals such as quenching of reactive oxygen species (ROS) and other oxidizing and/or redox compounds (Kaur et al, 2015 ; Barnabei et al, 2021 ; Jover-Mengual et al, 2021 ; Pogue and Lukiw, 2021 ); (ii) alteration of multiple phosphorylation events that disrupt the activation of the multi-subunit NF-kB transcription complex and alter the interaction of these phosphorylation sites that ultimately determines the selectivity of NF-κB effects on transcriptional activity (by advanced investigation of these highly interactive phosphorylation sites and mechanisms it should be possible to modulate or block many aspects of phosphorylation-mediated NF-kB activation; Christian et al, 2016 ; https://360researchreports.com/global-nf-kb-inhibitors-market-20149725 ); (iii) as previously pointed out, because active NF-kB complexes are assembled from various combinations of RelA, RelB, c-Rel, p50, p52, NFKB1 (p105) etc., it may be possible to specifically block the generation and/or assembly of a single monomeric species of NF-kB by limiting the abundance of one of the subunits of NF-kB by genome editing, including knock-out technologies and/or the Cas9/CRISPR editing system (Wang et al, 2018 ; Dai et al, 2020 ; Katti et al, 2022 ); (iv) NF-kB is directed to bind to its genomic targets by topological features located in certain promoter DNA sequences; therefore, these highly specific promoter DNA binding sites can be masked, blocked, or modulated using genome blocking technologies involving small non-coding RNA (sncRNA), NF-kB decoy sequence, and/or Cas9/CRISPR editing strategies (Taganov et al, 2006 ; Christian et al, 2016 ; Zhang et al, 2017 ; Baltimore, 2019 ; Dai et al, 2020 ; Katti et al, 2022 ; Yoon et al, 2022 ); (v) specific upregulated miRNA abundance and speciation may be blocked or modulated using chemically stabilized anti-miRNA strategies or by targeting miRNA processing enzymes, thus preventing the creation of a fully active and/or biologically available miRNA species; (vi) directed delivery systems to the brain and/or CNS or other tissue and/or organ systems to minimize unwarranted off-target effects; (vii) long-term systemic ingestion of low-dose NF-κB inhibitors including dietary-administered flavonoids, lignans, diterpenes and sesquiterpenes, saponins, polysaccharides, polyphenols, biological fiber, and other natural products that may have general beneficial effects on reducing pro-inflammatory signal...…”

“…(i) antioxidant approaches that neutralize the primary NF-kB activation signals such as quenching of reactive oxygen species (ROS) and other oxidizing and/or redox compounds (Kaur et al, 2015;Barnabei et al, 2021;Jover-Mengual et al, 2021;Pogue and Lukiw, 2021); (ii) alteration of multiple phosphorylation events that disrupt the activation of the multi-subunit NF-kB transcription complex and alter the interaction of these phosphorylation sites that ultimately determines the selectivity of NF-κB effects on transcriptional activity (by advanced investigation of these highly interactive phosphorylation sites and mechanisms it should be possible to modulate or block many aspects of phosphorylation-mediated NF-kB activation; Christian et al, 2016; https://360researchreports.com/global-nfkb-inhibitors-market-20149725); (iii) as previously pointed out, because active NF-kB complexes are assembled from various combinations of RelA, RelB, c-Rel, p50, p52, NFKB1 (p105) etc., it may be possible to specifically block the generation and/or assembly of a single monomeric species of NF-kB by limiting the abundance of one of the subunits of NF-kB by genome editing, including knock-out technologies and/or the Cas9/CRISPR editing system (Wang et al, 2018;Dai et al, 2020;Katti et al, 2022); (iv) NF-kB is directed to bind to its genomic targets by topological features located in certain promoter DNA sequences; therefore, these highly specific promoter DNA binding sites can be masked, blocked, or modulated using genome blocking technologies involving small non-coding RNA (sncRNA), NF-kB decoy sequence, and/or Cas9/CRISPR editing strategies (Taganov et al, 2006;Christian et al, 2016;Zhang et al, 2017;Baltimore, 2019;Dai et al, 2020;Katti et al, 2022;Yoon et al, 2022); (v) specific upregulated miRNA abundance and speciation may be blocked or modulated using chemically stabilized anti-miRNA strategies or by targeting miRNA processing enzymes, thus preventing the creation of a fully active and/or biologically available miRNA species; (vi) directed delivery systems to the brain and/or CNS or other tissue and/or organ systems to minimize unwarranted off-target effects;…”