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Introduction
NF-κB is ubiquitously expressed in peripheral and brain
cells and regulates the expression of a wide variety of genes
involved in cell survival, growth, stress responses, and
immune and inflammatory processes[1_3]. This factor was first
described by Sen and Baltimore in 1986 as a NF, that when
activated by agents, such as bacterial lipopolysaccharide,
bound to a 10 bp sequence in the enhancer region of the
gene encoding the k light chain (k) of antibody molecules
in B cells (B)[4]. NF-κB family members have been implicated
in the development of the nervous system and plasticity of
synapses[5_7]. NF-κB is persistently activated in cancer,
chronic inflammation, neurodegenerative diseases, stress,
stroke, trauma, heart disease, and other disease
conditions[8,9]. As NF-κB is an important regulator in programmed cell
death[10], it has been speculated that
NF-κB may play important roles in normal brain function and neurodegenerative
disorders[11,12].
NF-κB biology
c-Rel/NF-κB family NF-κB is composed of 5 members of
the c-Rel (Rel) family, including NF-κB1 (p50),
NF-κB2 (p52), RelA (p65), RelB, and Rel. All the Rel proteins contain a
conserved N-terminal region, called the Rel homology
domain (RHD). The N-terminal part of the RHD contains the
DNA-binding domain, whereas the dimerization domain is
located from C-terminal region of the
RHD[13]. Close to the C-terminal end of the RHD lies the nuclear localization signal
(NLS), which is essential for the transport of active
NF-κB complexes into the nucleus[14].
NF-κB family proteins are divided into 2 groups based on C-terminal sequences of the
RHD. The members of group 1 include NF-κB proteins p105
and p100, which are precursors of p50 and p52. Limited
proteolysis is required to produce p50 and p52. The second
group (the Rel proteins) mainly includes c-Rel (and its
retroviral homologue v-Rel), RelB, and RelA
(p65)[15]. All vertebrate NF-κB proteins can form homodimers or
heterodimers, except for RelB, which can only form
hetero-dimers. These homodimers and heterodimers that exhibit
differential binding specificities are p50/RelA, p50/c-Rel,
p52/c-Rel, p65/c-Rel, RelA/RelA, p50/p50, p52/p52, RelB/p50 and
RelB/p52[16]. The term NF-κB commonly refers specifically
to a p50_RelA (p50/p65) heterodimer, which is the
major Rel/NF-κB complex in most
cells[14].
NF-κB dimers are sequestered in the cytoplasm by a class
of inhibitor proteins, called IκB. In mammalian cells, the
major regulatory IκB proteins are IκB-α, IκB-β,
IκB-ε, and Bcl-3. The most common complex that is
activated in mammalian cells appears to involve
IκB-α, which binds to the p50/RelA heterodimer.
IκB function as inhibitors through ankyrin repeats that interact with the RHD in
NF-κB to mask the NLS and inhibit the nuclear translocation of
NF-κB. The N-termini of these IκB proteins constitute a signal
response domain, which is targeted for phosphorylation and
ubiquitination by a variety of stimuli. The
newly-synthesized IκB-α protein actively shuttles between the nucleus
and the cytoplasm and both inhibit nuclear import and
mediate the nuclear export of NF-κB/Rel proteins. In contrast, the
IκB-β protein can inhibit the nuclear import of
NF-κB/Rel proteins, but does not remove NF-κB/Rel proteins from the
nucleus[17,18].
NF-κB activation pathway Signals that induce
NF-κB
activity cause the phosphorylation of IκB thereby
activating the NF-κB complex. The activated NF-κB complex
translocates into the nucleus and binds to DNA at the
kB binding motifs and alters gene expression. Most signals that lead to
the activation of NF-κB act on a high molecular weight
complex containing a serine-specific IκB kinase (IKK). IKK
contains at least 3 distinct subunits: IKK-α,
IKK-β, and IKK-γ. IKK-α and IKK-β are catalytic kinase subunits, while
IKK-γ is a regulator for sensing and integrating upstream
activating signals[18]. There are 2
NF-κB activation pathways: the classical or canonical pathway and
the non-canonical pathway. In the canonical pathway, the activation of the
IKK complex leads to the phosphorylation of 2 specific
serines (Ser32 and Ser36) in IκB-α, which targets
IκB-α for ubiquitination and degradation by the 26S proteasome. In
the non-canonical pathway, the p100_RelB complex is
activated through phosphorylation by an IKK-α homodimer
(lacking IKK-γ) to generate p52_RelB. In either pathway, the
unmasked NF-κB complex can then enter the nucleus to
activate target gene expression. In the classical pathway, one
of the target genes activated by NF-κB can encode
IκB-α, and newly-synthesized IκB-α enters the nucleus
recombined with NF-κB, which can remove NF-κB from DNA, and export
the complex back to the cytoplasm to restore the original
latent state. Thus, the NF-κB activating pathway is a
transient process, generally lasting from 30 to 60 min in most
cells[20,21].
Dual roles of NF-κB in cell death and survival
NF-κB targets many genes to activate their expression.
These target genes include cytokines/chemokines and their
modulators, immunoreceptors, proteins involved in antigen
presentation, cell adhesion molecules, acute-phase proteins,
early response genes, stress response genes, cell surface
receptors, transcription factors and regulators, regulators of
apoptosis, growth factors, and cell death receptor ligands
and their modulators. In the central nervous system (CNS),
NF-κB can play an anti-apoptotic or pro-apoptotic role in
cell death[22]. This is not unexpected as
NF-κB regulates the genes involved in neuronal death and survival.
Anti-apoptotic activity of NF-κB A large number of
studies have demonstrated that NF-κB plays a prosurvival role
in proliferating cells, including tumor cells. Two actions of
NF-κB make it an important cell survival transcription factor
in these cells: the regulation of the cell cycle and the
inhibition of apoptosis. The best example for elucidating the
prosurvival action of NF-κB in cells is finding an inhibitory
role of NF-κB in death receptor-induced
apoptosis[23]. Binding to death receptors by
TNF-α activates caspase-8 through TRAF1 and NF-κB through TRAF2. The activation of
caspase-8 leads to apoptosis. Blocking NF-κB activation
potentiates TNF-α-induced apoptosis, indicating
NF-κB exerts anti-apoptotic action. It has been found that nerve growth
factor (NGF) promotes neuronal survival through activating
NF-κB[24]. Yu et
al[25] reported that mice lacking the p50
subunit of NF-κB exhibited increased damage to hippocampal
pyramidal neurons after the administration of the excitotoxin
kainate. In immortalized mouse hippocampal cell line HT22
cells, glutamate-induced apoptosis was inhibited by
IκB inhibitor aspirin, while the NF-κB decoy oligonucleotide
potentiated it[26]. The action of NF-κB on neuronal survival is
mediated through the upregulation of several prosurvival
genes.
Superoxide dismutase Manganese superoxide
dis-mutase (Mn-SOD) is an important antioxidant enzyme, which
is a potent scavenger of superoxide anion and is likely to
serve important cytoprotective roles against cellular damage.
It has been reported that NF-κB is involved in the
expression of Mn-SOD[27]. The incubation of human endometrial
stromal cells with TNF-α or the phorbol 12-myristate
13-acetate (TPA), a protein kinase C activator, caused marked
increases in nuclear NF-κB DNA binding activity and
Mn-SOD mRNA and activity. These effects of TNF-α and TPA
were completely inhibited by the proteasome inhibitor MG132
and the recombinant peptide capable of blocking
NF-κB nuclear translocation, SN50[28]. Activities of Mn-SOD and
SOD1 increased after spinal cord injury (SCI) and exposure
to neurotoxins[29,30]. The increase in SOD appeared to be
NF-κB-dependent, and overexpression significantly
protected against the deleterious effect of reactive oxygen
species, ceramide, or N-methyl-D-aspartate (NMDA).
Several other studies have shown that the overexpression of
copper-Zn SOD or the activation of Mn-SOD is
neuropro-tective against ischemia, excitotoxicity, and
Aβ toxicity[31_33].
Bcl-2 Bcl-2 and Bcl-XL are well-defined anti-apoptotic
proteins. The NF-κB binding site is identified in the
promoter of murine Bcl-x[34]. Bui et
al[35] found that NGF increased the expression of
Bcl-XL, possibly through the activation of
NF-κB. Some studies indicate that TNF-α has neuroprotective effects.
TNF-α increases the mRNA and protein levels of Bcl-2 and
Bcl-x[36]. It has also been found that the exposure of cultured neurons to
hypoxia/reoxygena-tion increases the levels of Bcl-2 and Bcl-X. The inhibition
of NF-κB activation abolished the hypoxia-induced
induction of Bcl-2 and Bcl-X, indicating that the induction of
Bcl-2 and Bcl-X is mediated by
NF-κB[37]. NF-κB is also reportedly involved in the activation of the Bcl-2 family member
A1/Bfl-1[38].
Pro-apoptotic activity of NF-κB A large number of
stu-dies have found that NF-κB activation participates in
neuronal apoptosis. The mechanism by which NF-κB
translocation induces apoptosis is not completely clear, but it is
assumed that this mechanism involves the regulation of 1 or
more genes known to play a pro-apoptotic role in apoptosis.
Among the NF-κB-responsive genes possibly involved in
the control of neuronal cell death, pro-apoptotic genes p53,
c-Myc, cyclin D1, Bcl-Xs, and the Fas ligand and its receptor
are activated by various pathological stimuli.
p53 The p53 protein is a tumor suppressor and plays
important roles in neuronal apoptosis via promoting the
expression of the pro-apoptotic gene Bax and PUMA, but
suppresses the expression of the cytoprotective gene Bcl-2.
NF-κB may contribute to neuronal apoptosis through the
induction of p53. In the study of glutamate receptor-mediated
excitotoxicity, upon stimulation of glutamate receptors, a
quick and robust induction in the levels of p53 mRNA and
protein was observed. The induction of p53 was blocked by
NF-κB inhibitors[39,40]. Qin et
al[40] investigated the role of
NF-κB in apoptosis induced by the NMDA receptor
agonists in rat striatal medium spiny neurons. The
administration of the excitotoxin quinolic acid and NMDA induced
apoptosis in the rat striatum. The inhibition of
NF-κB nuclear translocation by the SN50, a recombinant cell permeable
peptide containing the p50 nuclear localization sequence,
reduced apoptotic death of striatal neurons and p53 expression.
Uberti et al[41] pretreated the neuronal cultures with aspirin,
which inhibits NF-κB activation, or with a specific p53
antisense oligonucleotide, which inhibits p53 transcription,
resulting in a complete prevention of glutamate-induced p53
induction and apoptosis. The NF-κB-dependent induction
of p53 was also found in response to DNA damage and
oxidative stress. The induced p53 was apparently involved in
cell death under these conditions as the synthetic p53
inhibitor pifithrin-α blocked neuronal
apoptosis[42_45]. NF-κB not only regulates the levels of p53, but also increases the
stability of the DNA binding of p53, providing an additional
mechanism for promoting p53-mediated pro-apoptotic
signaling[46].
Cyclin D1 and c-Myc The cyclins are a family of
proteins that are involved in cell cycle progression and
apoptosis. The best explored link between NF-κB activation
and cell cycle progression involves cyclin D1, a cyclin which
is expressed relatively early in the cell cycle and is crucial to
DNA synthesis[47]. The NF-κB regulation of cyclin D1
occurs at the transcriptional level and is mediated by the
direct binding of NF-κB to multiple sites in the cyclin D1
promoter[48]. NF-κB promotes
G1 to S phase transition in mouse embryonic fibroblasts and in T47D mammary carcinoma
cells[49]. The NF-κB-mediated induction of cyclin D1 was
found in dorsal root ganglion neurons in response to
ceramide-induced apoptosis. The inhibition of
NF-κB blocked cyclin D1 induction and increased the viability of
neurons[50]. Liang et
al[44] reported that overstimulation
NMDA receptors with quinolinic acid induced a
NF-κB-dependent elevation in cyclin D1 mRNA and protein levels.
The incorporation of BrdU was observed in some neurons
undergoing apoptosis. NF-κB binding sites have also been
identified in the c-Myc exon and upstream sites and
positively regulate the expression of
c-Myc[51]. In excitotoxic models, c-Myc was upregulated through
NF-κB activation[39,44]. The NF-κB-dependent increase in c-Myc expression was also
observed in 6-hydroxydopamine-induced Parkinson's
disease[45,52].
The involvement of cell cycle regulators in neuronal
apoptosis has been shown by many investigators. The
expression of certain cell cycle regulators, such as cyclin D1,
cyclin G, c-Myc, and cdk4 have been found during neuronal
apoptosis[53_56]. To support the role of cell cycle regulators
in neuronal apoptosis, some studies showed that cdk
inhibitors blocked neurotrophic factor withdrawal-induced
apoptosis[57]. Cyclin D1 antisense or cell cycle inhibitors
and cdk inhibitors partially blocked the excitotoxin-induced
apoptosis of striatal neurons[44,58], suggesting cycle
regulators play an important role in neuronal apoptosis.
Bcl-Xs and BAX The bcl-x gene functions to regulate
cell death. Bcl-x transcripts are alternatively spliced into a
long and short form or the form lacking the transmembrane
domain. The long form (bcl-xL) represses cell death, while
the short form (bcl-xs) favors apoptosis.
NF-κB binding sites have been identified in the Bcl-x
promoter[59]. The NF-κB-dependent induction in Bcl-Xs has been reported. Dixon
et al[60] showed that following ischemia and
NF-κB activation, Bcl-xs messenger RNA levels increase in the CA1
hippocampal region. In cultured endothelial cells, hypoxia decreased
Bcl-2 mRNA levels, whereas the transfection of the
NF-κB decoy significantly attenuated a decrease in Bcl-2 mRNA,
increased Bcl-2/BAX ratio, and inhibited hypoxia-induced
cell death[61]. The prolonged activation of NMDA receptors
results in NF-κB nuclear translocation, release of LDH,
increases in the BAX/Bcl-XL ratio, and DNA fragmentation.
SN50 blocked the NMDA-induced increase in the
Bax/Bcl-XL ratio and cell
death[62]. Glutamate also reportedly increased
the expression of BAX, which was inhabitable with BAY
11-7082, a selective inhibitor of IκB-α
phosphorylation[63]. In cyanide-induced apoptosis, the expression levels of 2
anti-apoptotic Bcl-2 proteins, Bcl-2 and
Bcl-XL, remained unchanged after cyanide treatment, whereas the mRNA levels
of Bcl-Xs and Bax began to increase within 2 h, and their
protein levels increased 6 h after treatment. Both
NF-κB SN50 and the NF-κB decoy blocked the upregulation of
Bcl-Xs and BAX[64]. In low potassium-induced apoptosis of
cortical neurons, NF-κB DNA binding increased, and this
was accompanied by an elevation in Bcl-Xs transcription.
The latter was abolished by the inhibition of NF-κB or the
restoration of potassium levels[65].
Nitric oxide The role of nitric oxide (NO) in apoptosis is
complex, as it may exert proapoptotic or antiapoptotic
effects depending on experimental conditions.
NF-κB plays a role in regulating the expression of NO synthase (NOS). Xie
et al[66] defined a NF-κB binding domain in murine inducible
NOS (iNOS). NF-κB stimulated the expression of iNOS. The
NF-κB inhibitor pyrrolidine dithiolidin inhibited the
activation of NF-κB and the production of NO in
lipopolysaccharide (LPS)-treated macrophages, suggesting that the
activation of NF-κB/Rel is critical in the induction of iNOS by LPS.
NOS has been demonstrated to play a proapoptotic role
in several in vitro and in vivo studies. The incubation of
human breast cancer cell line MCF-7 cells and differentiated
neuronal PC12 cells with TNF-α increased the expression
and activity of iNOS. In addition to NOS inhibitors, iNOS
antisense oligonucleotides effectively prevented
NO2 generation and apoptosis, suggesting that the
TNF-α-induced cell death is mediated by iNOS-derived
NO[67,68]. Employing the intrastriatal injection of autologous blood in rats to model
intracerebral hemorrhage, Zhao et
al[69] demonstrated a robust and prolonged
NF-κB activation and a robust induction of iNOS at both the mRNA and protein levels. In SCI
models, iNOS was also found to be
increased[70], and the drugs inhibiting NOS offered protective
effects[71_73].
NF-κB inhibitors and neuroprotective therapy
Many human nervous system diseases have an
association with NF-κB activation. These conditions, including
aging[74], headache[75],
pain[76], stroke[77], traumatic brain
injury[78], SCI[79], Parkinson's
disease[80,81], multiple
sclerosis[82], Alzheimer's
disease[83,84], amyotrophic lateral
sclerosis[85], Huntington's
disease[86], and brain
tumors[87_91], have been associated with the
NF-κB pathway. As NF-κB plays important roles in regulating cell survival and death in a
broad array of physiological and pathological conditions,
it is an attractive proposal to manipulate NF-κB functions
to obtain its beneficial effects or abolish its harmful actions
when it is required[92]. Multiple signaling events are involved
in NF-κB activation, including the phosphorylation and
degradation of IκB, NF-κB nuclear translocation, and DNA
interaction, thus making it a relatively easy target for drug
actions (Figure 1). There are a large number of com-pounds
have been reported to inhibit NF-κB functions. These
compounds mainly include antioxidants, non-steroidal anti-inflammatory drugs (NSAID), flavonoids, protease inhibitors.
A few of these compounds have been used in the clinical
setting.
Antioxidants Oxidative stress is one of the common
pathogenic mechanisms in neurodegenerative disorders. Thus,
antioxidants are frequently employed in the treatment of
several neurodegenerative diseases, and are the most valuable
therapeutic strategy for fighting neurodegeneration.
Although it is hard to attribute a single mechanism to any
antioxidants' neuroprotective effects, the inhibition of
NF-κB activation is a prominent feature of antioxidants. The
antioxidants include N-acetyl-L-cysteine (NAC),
α-lipoic acid, glutathione monoester, pyrrolidine dithiocarbamate
(PDTC), tepoxalin, and flavonoids.
Free radicals are important mediators for NF-κB activation.
NAC, a well-characterized antioxidant, is found to exert
neuro-protective effects against free radical-related neuronal
injury[93,94]. NAC influences many cellular signaling pathways,
including c-Jun N-terminal kinase, p38 mitogen-activated
protein kinase, and redox-sensitive activating protein-1. NAC
can also prevent apoptosis and promote cell survival by
activating the extracellular signal-regulated kinase pathway.
NAC directly modifies the activity of several proteins by its
reducing activity[95], and is demonstrated to inhibit the
degradation of IκB-α and the activation of
NF-κB[96_98]. In animal models of global ischemia, pretreatment with NAC (300
mg/kg) or another antioxidant PDTC (200 mg/kg) significantly
reduced the infarct volume. NAC has also been reported to
increase the survival of dopaminergic neurons. The local or
systemic administration of NAC protected dopamine neurons
against 6-hydroxydopamine-induced oxidative
damage[99].
PDTC is an antioxidant that has been studied for many
years. Using cell cultures, Schreck et
al[100] found that
micromolar concentrations of PDTC reversibly suppressed
NF-κB activation. PDTC specifically prevented the
NF-κB-dependent transactivation of reporter genes under the
control of the HIV-1 long terminal repeat and simian virus 40
enhancer. In other studies, PDTC inhibited NF-κB
activation while enhancing the binding activity of activator
protein-1[101]. In addition, PDTC can inhibit the
NF-κB-mediated production of TNF-α, hypoxia-induced
dephosphorylation of Akt, and inflammatory
responses[102_104]. It has been shown that treatment with PDTC significantly attenuates
reperfusion-induced lung injury[105], glycerol-induced renal
injury[106], cholestatic liver
injury[107], and adriamycin-induced myocardial
apoptosis[108]. Crack et
al[109] observed that knockout glutathione peroxidase-1 (Gpx1) in mice increased the
ischemia-induced activation of NF-κB. PDTC was able to
afford partial neuropro-tection in the Gpx1-null mice. In Wistar
rats, PDTC prevented NF-κB activation in the ischemic brain,
as determined by the reduced DNA binding and nuclear
translocation of NF-κB in neurons. PDTC treatment reduced the
infarction volume by 48% when given 6 h after
MCAO[110].
Flavonoids are potent antioxidants found in many
natural products. They are widely used as food supplements
and as anti-inflammation and antitumor drugs. Recently,
many studies have demonstrated that flavonoids have
neuroprotective effects in animal
models[46]. Among them, Ginkgo
biloba has received particular attention. Chen
et al[111] found that Ginkgo
biloba extract significantly reduced intracellular reactive oxygen species formation and
NF-κB activation induced by TNF-α. Tea extracts have been
previously reported to possess radical scavenger, iron chelating,
and anti-inflammatory properties in a variety of tissues.
Recent studies found that green tea extracts were capable of
inhibiting NF-κB[112]. Studies demonstrated that green tea
extracts inhibited iron-induced lipid peroxidation,
NF-κB activation, and 6-hydroxydopamine (6-OHDA)-induced
neuronal death. 6-OHDA-induced apoptosis of
catecholaminergic PC12 cells was inhibited by green tea polyphenols and
their major effective component epigallocatechin-3-gallate
at a concentration of 200 mmol/L[113]. Green tea polyphenols
have been shown to reduce the toxic effects of β-amyloid,
ischemia/reperfusion-induced apoptosis, and the infarct
volume[114,115]. Given by brain penetrating property of
polyphenols, these compounds may be utilized as a class of
drugs for the treatment of neurodegenerative diseases.
IκB phosphorylation and degradation inhibitors
Phosphorylation and the subsequent proteasomal degradation
of IκB are key steps for NF-κB activation. NSAID and
cyclopentone prostaglandins are now found to be IκB
inhibitors. In 1994, Kopp and
Ghosh[116] reported that
sodium salicylate and aspirin inhibited the activation of
NF-κB through blocking the degradation of the IκB.
IKK-α and IKK-β phosphorylate IκB. Aspirin and sodium salicylate
can inhibit IKK-β activity in vitro and in
vivo. The mechanism by which aspirin and sodium salicylate inhibit
NF-κB
is the binding of these agents to IKK-β to reduce ATP
binding[117]. These studies not only further explain the new
mechanism of actions, but also suggest new implications of these
drugs. Grilli et al[118] found that acetylsalicylic acid and its
metabolite sodium salicylate protected neurons against
neurotoxicity elicited by the excitatory amino acid glutamate in
rat primary neuronal cultures and hippocampal slices. This
inhibitory effect may be involved in the inhibition of
NF-κB activation, protein kinase C zeta activity, superoxide anion
generation, and lipid
peroxidation[118_120]. Recent studies
suggest that aspirin and other NSAID protected cultured
mesencephalic cells against 6-OHDA, 1-methyl-4
phenylpyri-dinium, and glutamate-induced
toxicity[121,122]. Using NSAID in Parkinson's disease (PD) has also been
proposed[123]. It has been found that arthritis patients taking aspirin have a
lower incident and later onset of Alzheimer's disease (AD).
Emerging evidence shows that aspirin and other NSAID have
multiple influences on the AD pathogenic process,
including inhibiting the formation of fibrillar Aβ, destabilizing
preformed fibrillar β-amyloid (Aβ), and preventing the
aggregation of Aβ and attenuating its
toxicity[124_126]. Recent studies also indicate that acetylsalicylic acid inhibits tau
phosphorylation[127]. Other potentially interesting anti-inflammatory
drugs have also been reported to exert neuroprotective
effects and inhibit NF-κB, including cannabinoid dexanabinol
and caffeic acid[128_130].
Recent studies have identified that cyclopentenone
prostaglandins (cPG), including prostaglandin (PG)A1 and PGJ2
are ligands for peroxisome-proliferation activator
receptor-γ and inhibitors of NF-κB. Rossi et
al[131] reported that PGA1 could block
NF-κB activation by inhibiting IκB phos-phorylation. In a subsequent study, they further identified
that PGA1 could directly inhibit IκB
kinase-β[132]. PGA1 also increases the expression of
IκB-α[133]. Similar inhibitory
effects of PGJ2 and PGE1 on NF-κB were
observed[134_136]. In addition, PGJ2 was found to interfere with DNA binding
through covalently modifying the NF-κB p50
subunit[137]. Thus, cPG inhibit NF-κB by interfering in multiple sites in
the NF-κB signaling pathway from IκB synthesis to DNA
binding[138]. Studies have shown that cPG have
neuropro-tective effects under certain pathological con-ditions. Qin
et al[139] first reported that PGA1 protected striatal neurons
against NMDA receptor agonist quinolinic acid-induced
apoptosis through inhibiting NF-κB activation. PGA1 also
inhibited the mitochondrial toxin rotenone-induced death of
dopaminergic cell line SH-SY5Y
cells[140]. In recent studies, PGA1 and PGJ2 were reported to reduce ischemic brain
damage through inducing heat shock proteins, inhibiting
NF-κB activation, and
inflammation[141_143]. These studies revealed
that the administration of PGA1 and PGJ2 2_3 h
post-ischemia was still effective. Other studies have also reported
that PGJ2 reduced ischemic myocardial
infarction[144].
Other drugs, such as estrogen, curcumin, and quercetin
have been reported to inhibit IκB
degradation[145_148]. All these compounds are reported to have neuroprotective
effects under certain experimental conditions.
NF-κB nuclear translocation and DNA binding
inhibitors NF-κB has to translocate into the nucleus in order to
regulate gene expression. Drugs acting on NF-κB nuclear
transport and DNA binding have received considerable
attention. Lin et al[149] synthesized a membrane-permeable
recombinant peptide NF-κB SN50. This peptide contains a
signal peptide, which confers the cell membrane
permeability of SN50, and a nuclear localization signal, which
competes with NF-κB for nuclear entry. The peptide inhibits the
nuclear translocation of NF-κB in cultured endothelial and
monocytic cells stimulated with LPS or TNF-α in a
concentration-dependent manner. This peptide has been widely
used for dissecting cellular functions of
NF-κB[150,151]. We, along with others, have successfully used SN50 for
inhibiting NF-κB nuclear import in vivo and have found that it is
very effective in blocking NF-κB nuclear entry and
NF-κB-mediated target gene transcription in response to various
stimuli[39,44,45,150,152_156]. An intrastriatal or nigral injection of
SN50 substantially inhibited the nuclear translocation of
NF-κB, inhibiting the expression of NF-κB target genes p53,
c-Myc and cyclin D1, and attenuating
excitotoxicity[39, 44,45,153]. One study has successfully blocked
cholecystokinin-octapeptide-induced pancreatitis with an intraperitoneal
injection of SN50[155]. These studies suggest that nuclear import
inhibitors represent an important class of NF-κB inhibitors.
Many studies have focused on NF-κB DNA decoys. The
NF-κB DNA decoys are double-stranded DNA
oligonucleotides (ODN) containing the NF-κB-binding motif. When
delivered to cells, it competes with NF-κB for DNA binding
sites, and thus inhibits NF-κB function. Some studies have
demonstrated that ODN that are delivered locally or
systemically are effective in blocking NF-κB transactivation
activity[157_160]. Some in vivo therapeutic studies with ODN
have generated promising results. The systemic
administration of ODN suppressed NF-κB activity, and the expression
of cytokines protected liver grafts against
ischemia/reperfusion-induced injury in
rats[161]. The animal studies showed that
NF-κB decoys reduced lung vascular permeability in septic mice, improved lung
function[162], and inhibited hepatic metastasis in the mice loaded with murine
reticulosarcoma M5076[163]. The clinical usefulness of ODN
has been tested in 2 patients with percutaneous coronary
intervention. The initial results showed the suppression of
restenosis with no observed adverse
effect[164]. NF-κB
decoys may be a potential therapeutic strategy for certain
types of diseases[165,166].
Drugs that directly inhibit NF-κB DNA binding have been
found, but have not been well characterized. For example, it
has been reported that the metal-chelating drug aurine
tricarboxylic acid inhibited NF-κB DNA
interaction[167].
Neurological disorders may benefit from NF-κB inhibitors
Ischemic brain injury The distribution of
NF-κB was investigated immunohistochemically in post-mortem brains
of stroke patients. An enhanced immunoreactivity of
NF-κB was observed in glial cells of infarcted areas, particularly in
the penumbra or border zone between the ischemic and
non-ischemic areas[168]. In animal studies, early activation of
NF-κB has been found to precede DNA damage after ischemic
attack[169,170]. It was reported that ischemia induced a
TNF-like weak inducer of apoptosis (TWEAK) and its membrane
receptor Fn14. TWEAK promotes neuronal cell death and
activates NF-κB through the upstream kinase
IKK[171]. The deletion of the neuronal IKK2 subunit or inhibition of IKK
activity reduced the infarct size and neuronal cell loss. The
role of NF-κB in neuronal death was further suggested, as
several neuroprotective agents, such as antioxidant
LY231617, PDTC, and PGA1, have been shown to inhibit
NF-κB activation, reduce infarct volume, and improve
behavior deficits[110,173,174]. The contribution of
NF-κB activation to ischemic neuronal damage has also been assessed
with either the expression of mutant IκB-α in neurons and
glial, or NF-κB p50 knockout mice and transgenic mice. The
results indicated that the neuronal expression of the
NF-κB inhibitor reduced both the infarct size and cell
death[174]. Mice lacking the p50 subunit of
NF-κB develop significantly smaller infarcts after transient focal
ischemia[173,175]. These studies may have established the rationale for use of
NF-κB inhibitors in ischemic brain injury.
PD Recently, the role of the neuron-glia interaction and
the inflammatory process in PD has been the focus of
intense study by the research community. The increase in
NF-κB has been found in the post-mortem brains of PD patients.
In PD patients, the proportion of nigral dopaminergic
neurons with immunoreactive NF-κB and interferon-γ was
significantly increased in comparison with control
patients[81,176]. A possible relationship between the nuclear localization of
NF-κB in the mesencephalic neurons of PD patients and
oxidative stress in such neurons has been shown
in vitro with primary cultures of rat mesencephalon, where the
translocation of NF-κB is preceded by a transient production of
free radicals during apoptosis induced by the activation of
the sphingomyelin-dependent signaling pathway with
C2-ceramide. The data suggest that this oxidant-mediated
apoptogenic transduction pathway may play a role in the
mechanism of neuronal death in PD[176]. In animal models of
PD, the inhibition of NF-κB achieves neuroprotection against
the 6-OHDA- and MPTP-induced degeneration of
dopaminergic neurons[44,45,112,177], suggesting that
NF-κB inhibitors could be beneficial in PD.
AD The distribution of NF-κB was investigated
immuno-histochemically in the post-mortem cases of AD. In the AD
cases, increased staining for NF-κB p65 was seen in neurons
and their processes, neurofibrillary tangles, and dystrophic
neurites. The neuronal staining observed in AD was
strongest in the hippocampal formation and entorhinal
cortex[178]. Boissière et
al[179] studied the cellular distribution of
NF-κB in the nucleus basalis of Meynert of AD and control patients.
The proportion of large cholinergic neurons with elevated
nuclear immunostaining of NF-κB was significantly increased
in AD, suggesting an association between NF-κB functions
and the process of cholinergic degeneration in AD. In
another report, NF-κB immunoreactivity was found in the
neutrophil of diffuse Aβ deposits. In addition,
NF-κB immunoreactivity was found in the nuclei of neurons, but not in
the nuclei of reactive astrocytes, in the vicinity of diffuse
plaques[180]. The discovery of NF-κB activation in AD has
been confirmed by other
investigators[181_183]. Since inflammation is a prominent feature in AD,
NF-κB may participate in the inflammatory response. A more direct connection of
AD pathogenesis and NF-κB was observed as Aβ activates
NF-κB[184_186]. Although an early in
vitro study found that the activation of NF-κB by a low dose of
Aβ may have neuroprotective
effects[187], other studies have been observed
that NF-κB inhibitors inhibit the production of
Aβ[188]. In rat primary neurons and human post-mitotic neuronal cells, the
Aβ peptide induced dose-dependent neuronal death, the
nuclear translocation of the p65 and p50 subunits, and an
apoptotic profile of gene expression. The anti-inflammatory
drug aspirin and the selective IκB kinase 2 inhibitor AS602868
completely inhibited p50/p65 nuclear translocation and
neuronal damage[189]. The clinical trials with some NSAID did
not generate encouraging outcomes, as noted by Valerio
et al[190], since not all NSAID can inhibit
Aβ production. Better compounds with the ability to reduce
Aβ should be selected in future studies.
Excitotoxicity Excitotoxicity has been implicated in
several neurodegenerative diseases. Kaltschmidt
et al[191] reported that the ionotropic glutamate receptor agonist kainic
acid (KA) activates NF-κB. Later studies defined a
pro-apoptotic role of NF-κB activation and nuclear translocation
mediated by AMPA/KA receptors[153,192]. Similarly, the
stimulation of glutamate NMDA receptors robustly activates
NF-κB through the degradation of
IκB-α[139,152]. In other studies, the pharmacological upregulation of
NF-κB increased glutamate-induced excitotoxicity, while the
upregulation of CREB decreased
excitotoxicity[193]. Grilli et
al[118] reported a neuroprotective role of aspirin on the
glutamate-induced death of hippocampal neurons, opening
a new avenue for the study of excitotoxicity. Since then,
several studies have reported that the inhibition of
NF-κB has neuroprotective effects. In studies conducted by Casper
et al[121], neuroprotection against glutamate-mediated
excitotoxicity was also found with ibuprofen. The inhibition
of NF-κB with a herbal active component glycyrrhiza
acid[193], free radical scavenger
OCT14117[194], and glutamate metabo-tropic receptor agonists
(2S,
1'S,2'S)-(carboxy-cyclopropyl)glycine and amino-4-phosphonobutyric
acid[195] was associated with a neuroprotective effect. These results suggest
that NF-κB inhibitors could be suitable drugs for blocking
excitotoxicity.
Summary
The signaling pathway and the role of NF-κB have been
studied for more than 2 decades. However, we still have
limited knowledge on the role of NF-κB in CNS neurons and
the molecular mechanisms underlying its actions. Many
controversial findings need to be consolidated. In particular, its
dual roles in neuronal death and survival and underlying
molecular mechanisms need to be carefully evaluated in
relation to human neurological
diseases[197_200]. The involvement of
NF-κB in human diseases certainly establishes it as
a potential target for therapy. Many common synthetic (eg
aspirin) and traditional remedies target, at least in part, the
NF-κB signaling. Our knowledge of the molecular details of
the NF-κB pathway will enable us to develop more specific
NF-κB inhibitors to treat neurological diseases.
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