- 6 Role of NF- κ B in Brain Diseases. - The diseases in which abnormal NF-κB regulation has been reported to play significant roles include atherosclerosis, AIDS, tumors, diabetes, heart dis- eases, muscular dystrophy, rheumatoid arthritis, inflammatory bowel diseases, bone resorption, and some neurodegenerative diseases reviewed by (Kumar et al., 2004).. - 6.1 Role of NF- κ B in Ischemic and Traumatic Brain Injury. - Transient global forebrain ischemia causes NF-κB activation in CA1 hippocampal neurons (Clemens et al., 1997). - A delayed increase in NF-κB activa- tion in association with reactive glial cells was also observed several days after focal ischemia/reperfusion (Gabriel et al., 1999). - Studies of mice lacking the p50 subunit of NF-κB suggest that, overall, NF-κB activation enhances ischemic neuronal death, but its effects differ among different cell types (Schneider et al., 1999). - In cultured neuronal cells, activation of NF- κ B protects them against excitotoxic and metabolic insults relevant to the pathogenesis of stroke, including glucose deprivation and exposure to glutamate (Cheng et al., 1994. - Yu et al., 1999). - The cortical and striatal neu- rons of mice that fail to induce the κB-responsive Mn-superoxide dismutase (SOD) gene due to lack of TNF-α receptors are more vulnerable to focal ischemic injury (Schmidt-Ullrich et al., 1996). - The neuroprotective effect of endogenous TNF-α is likely mediated by NF-κB activation in neurons, because mice lacking p50 and mice treated with κB decoy DNA exhibit increased vulnerability of hippocampal neurons to excitotoxicity (Yu et al., 1999). - The IκB kinase complex (IKK) is also activated in a mouse model of stroke and appears to play a key function in ischemic brain damage (Herrmann et al., 2005). - In contrast, constitutive activation of IKK2 enlarges the infarct size (Herrmann et al., 2005). - NF-κB activation also occurs in the cerebral cortex within hours of traumatic brain injury in rats, and this activation becomes maximal within the first 24 h (Nonaka et al., 1999. - Sanz et al., 2002). - In addition, expression of IκBα is also observed in astrocytes and microglial cells of the corpus callosum in traumatic brain injury at the time of NF-κB activation (Sanz et al., 2002).. - 6.2 Role of NF- κ B in Seizures. - In laboratory animals, NF- κ B activity is rapidly increased in hippocampal neurons within 4–6 h after kainate-induced seizures, which is followed by a delayed and sustained NF-κB activation in glial cells (Yu et al., 1999). - In mice lacking the p50 subunit of NF-κB, which is required for the vast majority of κB DNA-binding activity in the hippocampus, seizure-induced neuronal degeneration is greater than in control mice (Yu et al., 1999). - Neuronal NF- κ B activation can stabilize intracellular calcium con- centrations under ischemia-like conditions (Barger et al., 1995. - Barger and Mattson, 1996), possibly via induction of several different genes, including those encoding calcium-binding proteins and glutamate receptor (Cheng et al., 1994. - Gary et al., 2000).. - 6.3 Role of NF- κ B in Alzheimer Disease (AD). - Recent studies suggest that dysregulation of NF-κB signaling might be involved in the pathogenesis of AD. - NF-κB immunoreactivity is found especially in and around the early senile plaques in AD brain, whereas mature plaques show mainly reduced NF-κB activity (Kaltschmidt et al., 1999). - Several reports suggest that amyloid β (Aβ) peptide can activate NF-κB in neurons, suggesting a plausible mechanism by which Aβ may act in AD (Barger et al., 1995). - Actually, elevation and activation of p65 and p50 subunits of NF- κ B have been observed in AD brain (Yan et al., 1995;. - Boissiere et al., 1997. - Kaltschmidt et al., 1997). - Activation of NF-κB protects hip- pocampal neurons against oxidative stress-induced apoptosis (Mattson et al., 1997).. - On the other hand, inhibition of NF-κB potentiates Aβ-mediated neuronal apoptosis (Kaltschmidt et al., 1999). - The proapoptotic protein prostate–apoptosis response- 4 (Par-4), which is implicated in AD, kills neurons partially by inhibiting NF-κB activity (Guo et al., 1998a). - Interestingly, expression of IκB-α, IκB-γ and its pre- cursor, p105, are also increased in AD brain (Yoshiyama et al., 2001. - Huang et al., 2005), and the increased IκBα expression is in a distribution that corresponds to the neurofibrillary pathology of AD (Yoshiyama et al., 2001).. - It is interesting that a low dose (0.1 μM) of Aβ is able to activate NF-κB and to protect against a high cytotoxic dose (10 μM) of Aβ (Kaltschmidt et al., 1999).. - This finding actually led to the discovery of an essential role for NF- κ B in precon- ditioning (Blondeau et al., 2001. - Ravati et al., 2001). - General evidence suggests that con- stitutive NF-κB activity is essential for neuronal survival (Bhakar et al., 2002). - Activation of neuronal NF-κB in AD may be a neuroprotective response, but activation of NF-κB in glial cells may mediate the production of proinflammatory cytokine and nitric oxide associated with the amyloid and neurofibrillary pathol- ogy in AD (Chen et al., 2005. - Ho et al., 2005). - NF-κB might also play a role in amyloidogenesis of AD, because the enhancer region 5 to the APP gene contains NF-κB–binding sites, and expression of APP can be induced by NF-κB (Grilli et al., 1996). - A recent report suggests that NF-κB activation may also mediate sAPPα release (Choi et al., 2006).. - Presenilin-1 mutations impair the ability of neurons to induce NF- κ B activation under conditions of oxidative stress in the pathogenesis of AD (Guo et al., 1998b).. - Transgenic mice with presenilin mutation exhibit impaired NF-κB activation in response to exposure to trimethyltin (Kassed et al., 2003).. - 6.4 Role of NF- κ B in Parkinson’s Disease (PD) and Huntington’s Disease (HD). - It is striking that there is a seventyfold increase in the percentage of dopaminergic neurons with nuclear immunoreactive NF-κB p65, which indicates NF-κB activation, in the substantia nigra of PD patients as compared to age-matched controls (Hunot et al., 1997). - This observation suggests a role of NF-κB activa- tion in PD. - NF-κB activity increased in affected neurons in the substantia nigra and striatum may represent an early protective response to ongoing oxidative stress and mitochondrial dysfunction (Browne et al., 1999. - Consistent with this is that an NF-κB inhibitor increases the vulnerability of dopaminergic neurons to Parkinsonian neurotoxin 6-hydroxydopamine (Park et al., 2004). - Mice lacking the p50 subunit of NF-κB exhibit increased damage to striatal neurons and worsened motor dysfunction after administration of the mitochondrial toxin 3-nitropropionic acid in an HD animal model (Yu et al., 2000). - However, NF- κ B activation may also promote the death of neurons under conditions such as oxidative and metabolic stress that often occur in neurodegener- ative diseases (Schneider et al., 1999. - In a neuronal cell line, mutant huntingtin is found to activate NF- κ B, and blockage of the NF- κ B acti- vation reduces the toxicity of the mutant huntingtin (Khoshnan et al., 2004). - Microglial activation has been shown to contribute to neu- ronal death in PD, and this activation may be mediated by the NF-κB/p38 MAPK pathway (Wilms et al., 2003).. - 6.5 Role of NF- κ B in Multiple Sclerosis. - Although the molecular mechanism of oligodendrocyte depletion is not well understood, increased levels of TNF- α and IL-1 β transcripts and activation of NF- κ B have been observed in active multiple sclerosis lesions (Gveric et al., 1998. - Bonetti et al., 1999). - In CNS glial cells treated with proinflammatory cytokine, inhibition of NF-κB transactivation by IL-4 protects differentiating oligodendrocyte progenitors (Paintlia et al., 2006). - This observation further supports a role of NF- κB in the pathogenesis of multiple sclerosis. - This infection directly induces proinflammatory cytokines in primary astrocytes via NF-κB activa- tion (Palma et al., 2003), suggesting that NF-κB is critical for the development of immune-mediated demyelination. - Genetic studies demonstrate that inhibitors of the NF-κB cascade comprise prime candidate genes predisposing to multiple sclerosis (Miterski et al., 2002). - NF-κB also regulates transcription of myelin basic protein gene in oligodendroglioma cells (Huang et al., 2002).. - The first evidence that NF-κB pathways could be inhib- ited came from studies of IκB-α mutant that could not be phosphorylated by IKK and thus not degraded by proteasome (Ghosh et al., 1998). - Delivering this IκB-α suppressor mutant by adenoviral vec- tors has been effective in rheumatoid arthritis models (Bondeson et al., 1999) and in reducing the resistance of tumors to chemotherapy in a mouse model (Wang et al., 1999). - Panwalker et al., 2004. - These protective actions are mediated by blocking endothelial NF-κB (Zhang et al., 2006). - In a mouse model of stroke, a selective small molecule inhibitor of IKK reduces the infarct volume and cell death in a therapeutic window of 4.5 h (Herrmann et al., 2005). - A natural green tea constituent, (–)-epigallocatechin-5-gallate, can limit brain inflammation and reduce neuronal damage via inhibiting NF- κ B overactivation in an animal model of autoim- mune encephalomyelitis, which opens a new therapeutic avenue for inflammatory brain diseases (Aktas et al., 2004).. - Some naturally occurring and synthetic inhibitors of ubiquitin-proteasome also block NF-κB activation by pre- venting IκB degradation (Adams et al., 2000). - For example, inhibitors of NF- κ B that selectively target. - Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R et al (2004) Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotec- tion in autoimmune encephalomyelitis. - Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J et al (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. - Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK et al (2002) Control of synaptic strength by glial TNFalpha. - Bhakar AL, Tannis LL, Zeindler C, Russo MP, Jobin C et al (2002) Constitutive nuclear factor- kappa B activity is required for central neuron survival. - Boissiere F, Hunot S, Faucheux B, Duyckaerts C, Hauw JJ, Agid Y et al (1997) Nuclear translo- cation of NF-kappaB in cholinergic neurons of patients with Alzheimer’s disease. - Bonetti B, Stegagno C, Cannella B, Rizzuto N, Moretto G et al (1999) Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. - Burkly L, Hession C, Ogata L, Reilly C, Marconi LA et al (1995) Expression of relB is required for the development of thymic medulla and dendritic cells. - Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C et al (1998) Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. - Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R et al (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75.. - Proc Natl Acad Sci USA Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S et al (2005) SIRT1 protects against. - Choi S, Kim JH, Roh EJ, Ko MJ, Jung JE et al (2006) Nuclear factor-kappa B activated by capacita- tive Ca2+ entry enhances muscarinic receptor-mediated sAPPalpha release in SH-SY5Y cells.. - Cell Death Differ Dajee M, Lazarov M, Zhang JY, Cai T, Green CL et al (2003) NF-kappaB blockade and oncogenic. - Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K et al (1992) The candidate oncopro- tein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. - Nature Freudenthal R, Locatelli F, Hermitte G, Maldonado H, Lafourcade C et al (1998) Kappa-B like. - Grilli M, Ribola M, Alberici A, Valerio A, Memo M et al (1995) Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. - Guo Q, Fu W, Xie J, Luo H, Sells SF et al (1998a) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. - Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W et al (2005) IKK mediates ischemia-induced neuronal death. - Mol Cell Biol Huang CJ, Nazarian R, Lee J, Zhao PM, Espinosa-Jeffrey A et al (2002) Tumor necrosis factor. - Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP et al (1997) Nuclear translocation of NF- kappaB is increased in dopaminergic neurons of patients with parkinson disease. - Kaltschmidt B, Linker RA, Deng J, Kaltschmidt C (2002) Cyclooxygenase-2 is a neuronal target gene of NF-kappaB. - Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L et al (2006) NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. - Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y et al (2001) Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. - Kassed CA, Butler TL, Navidomskis MT, Gordon MN, Morgan D et al (2003) Mice expressing human mutant presenilin-1 exhibit decreased activation of NF-kappaB p50 in hippocampal neurons after injury. - Kassed CA, Butler TL, Patton GW, Demesquita DD, Navidomskis MT et al (2004) Injury- induced NF-kappaB activation in the hippocampus: implications for neuronal survival. - Mol Cell Khoshnan A, Ko J, Watkin EE, Paige LA, Reinhart PH et al (2004) Activation of the IkappaB. - Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH et al (2000) The RelA NF- kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. - Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R et al (1995) Mice lacking the c-rel proto- oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. - Kovacs AD, Chakraborty-Sett S, Ramirez SH, Sniderhan LF, Williamson AL et al (2004) Mechanism of NF-kappaB inactivation induced by survival signal withdrawal in cerebellar granule neurons. - Liou HC, Jin Z, Tumang J, Andjelic S, Smith KA et al (1999) c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. - Lipsky RH, Xu K, Zhu D, Kelly C, Terhakopian A et al (2001) Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection. - Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A et al (2001) Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. - Miterski B, Bohringer S, Klein W, Sindern E, Haupts M et al (2002) Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations
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