Table I.
Drugs that prevent and treat Alzheimer's disease through the NF-κB signaling pathway.
| First author, year | Compound and original source | In vivo model | In vitro model | Dose and drug administration time | Targets | Signaling pathways | (Refs.) |
|---|---|---|---|---|---|---|---|
| Sun et al, 2021 | Rutin/- | Tau-P301S mice | Tau oligomers-induced primary microglia |
In vivo: 100 mg/kg-30 days In vitro: 8 μM-24 h |
↓: Tau aggregation, tau-mediated cytotoxicity, IL-1β, TNF-α, tau oligomer-induced toxicity, tau pathology, GFAP, Iba-1, IKK-β, p-P65/P65, synapse loss, microglial synapse engulfment ↑: microglial engulfment of extracellular tau, PP2A |
NF-κB | (51) |
| Gu et al, 2018 | PL/Piper longum | LPS-induced ICR mice | LPS-induced BV2 cells |
In vivo: 1.5,3 mg/kg; 7 days In vitro: 0.5, 1, 2.5 μM; 18 h |
↓: Aβ1-42, activities of β-secretase and γ-secretase, APP, BACE1, COX-2, iNOS, GFAP, Iba-1, NF-κB translocation, phosphorylated-IκB, TNF-α, IL-1β, IL-6 ↑: neuronal survival |
NF-κB | (53) |
| Gu et al, 2015 | BV/Bee | LPS-induced ICR mice | LPS-induced BV2 cells |
In vivo: 0.8, 1.6 μg/kg; 7 days In vitro: 0.5, 1, 2 μg/ml; 48 h |
↓: Aβ1-42, β-secretase and γ-secretase, APP, BACE1, COX-2, iNOS, GFAP, Iba-1, neuronal death, NF-κB translocation, p-IκB | NF-κB | (55) |
| Kim et al, 2017 | PUN/pomegranate | LPS-induced ICR mice | LPS-induced BV2 cells |
In vivo: 1.5 mg/kg; 7 days In vitro: 10, 20, 50 μM; 24 h |
↓: Aβ1-42, BACE1, GFAP, Iba-1, TNF-α, IL-1β, IL-6, MDA, ROS (H2O2), COX-2, iNOS, NF-κB translocation, p-IκB, NF-κB DNA binding activity ↑: GSH/GSSG |
NF-κB | (57) |
| Chen et al, 2020 | TEN/Polygala tenuifolia Willd | - | Aβ42-induced BV2 cells | In vitro: 1, 5, 10 μM; 24 h | ↓: TNF-α, IL-1β, IL-6, COX-2, iNOS, NF-κB translocation | NF-κB | (58) |
| Shahbazi et al, D 2020 | 4/black and white pepper | - | LPS-induced human microglia clone 3 | In vitro: 0.86 μM; 24 h | ↓: NO, iNOS, TNF-α, IL-1β, PPAR-γ, IKK-α, IkB-α, NF-kB p65 | NF-κB | (61) |
| Park et al, 2015 | BFE/BF | LPS-induced C57BL/6 mice | LPS-induced BV2 cells |
In vivo: 30 mg/kg; 3 days In vitro 10 μg/ml; 4 h |
↓: NO, iNOS, TNF-α, IL-1β, IL-6, NF-κB p65/RELA, GFAP, Iba-1 | NF-κB | (63) |
| Leláková et al, 2020 | MF/Macaranga siamensis | - - |
LPS-induced THP-1 and THP-1-XBlue™ -MD2-CD14 human monocytes, BV2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia | In vitro: 1 μmol/l; 18 h | ↓: TNF-α, IL-1β, NF-кB, AP-1, degradation of IкBα | NF-κB | (64) |
| Yeo et al, 2020 | miconazole (MCZ)/- | LPS-induced C57BL 6/N mice Aβ1–42-induced mice with AD | LPS-induced BV2 cells |
In vivo: 40 mg/kg; 7/14 days In vitro: 1.25, 2.5, 5, 10 μM; 24 h |
↓: TNF-α, IL-1β, IL-6, COX-2, iNOS, GFAP, Iba-1, NO, p-IκB, NF-κB translocation | NF-κB | (66) |
| Solberg et al, 2014 | LD55/- | AβPP/PS-1 transgenic mice with AD | - | In vitro: a diet containing 100 ppm LD55; 12 months | ↓: Aβ plaques, activated microglia | NF-κB | (67) |
| Lindsay et al, 2021 | GA/GILZ | 5XFAD mice | - | In vivo: 100 μl GA; alternate days for 6 weeks | ↓: Aβ plaque burden, NF-κB p65, IL-1β, IL-12, IL-6, IFN-γ, GFAP, Iba-1, CD14, TLR-2, TLR-4 | NF-κB | (68) |
| Choi et al, 2018 | K284-6111/- | Aβ1-42-induced mice with AD | LPS-induced BV2 cells |
In vivo: 3 mg/kg; 4 weeks In vitro: 0.5, 1, 2 μM; 24 h |
↓: CHI3L1, iNOS, GFAP, Iba-1, TNF-α, IL-1β, IL-6, Aβ1-42, APP, BACE1, C99, p-IκB, NF-κB translocation | inactivation of NF-κB-mediated CHI3L1 | (69) |
| Ham et al, 2020 | Tg2576 mice | Aβ-induced BV2 cells |
In vivo: 3 mg/kg; 4 weeks In vitro: 0.5, 1, 2 μM; 24 h |
↓: Aβ1-42, Aβ1-40, APP, BACE1, β-secretase, COX-2, iNOS, GFAP, Iba-1, Cd86, p-IκBα, p-ERK1/2, p-JNK, CHI3L1, PTX3 | ERK-mediated PTX3 and NF-κB | (16) | |
| Lian et al, 2017 | DL0410/- | D-gal-induced ICR mice | - | In vivo: 1, 3, 10 mg/kg; 4 weeks | ↓: AChE activity, AGEs, MDA, mitochondria structure, Iba-1, GFAP, RAGE, p-P65, COX2, iNOS, p-JNK, cleaved caspase 3, cleaved PARP ↑: ACh level, TEACl, activities of catalase, GPx, SOD, OPR, the number of synapses |
RAGE/NF-κB | (70) |
| Zhong et al, 2019 | EGCG/green tea | APP/PS1 double transgenic mice with AD | LPS-induced BV2 cells Aβ1-42-induced primary microglia |
In vivo: 2 mg/kg; 4 weeks In vitro: 10 μM; 1 h |
↓: caspase-1 p20, NLRP3, caspase-11 p26, TLR4, p-IKK/IKK, p-NF-κB/NF-κB, Iba-1, IL-1β, IL-18 | TLR4/NF-κB | (80) |
| Zhou et al, 2014 | Gen/SIF | - | Aβ25–35-induced BV2 cells | In vitro: 12.5, 25, 50, 100, 200 μM; 26 h | ↓: IL-1β, iNOS, TLR4, NF-κB p65, NF-κB p50, DNA-binding activity of NF-κB ↑: cell viability, IL-10 |
TLR4/NF-κB | (81) |
| Chen et al, 2021 | Oxysophoridine/Sophora alopecuroides L. seeds | - | Aβ1-42-induced BV2 cells | In vitro: 0, 2.5, 5, 10, 20, 40 μM; 48 h | ↓: MDA, TNF-α, IL-1β, TLR4, MyD88, NF-κB p65 ↑: activities of GPx, CAT, and SOD |
TLR4/NF-κB | (82) |
| Zeng et al, 2012 | PTA/Caesalpinia sappan L. | - | LPS-induced BV2 cells | In vitro: 5, 10, 25, 50 μM; 10 min | ↓: Total ROS, gp91 phox, MDA, iNOS, NO, Nitrotyrosine, Iba-1, p-NF-κB p65 on serine-536, p65 and p50 translocations, IKKα/β, p-IκB, the interaction of TLR4 with MyD88, IRAK1 and TRAF6, interaction of LPS with TLR4 ↑: synapse remodeling |
CD14/TL R4-dependent NF-κB | (88) |
| Capiralla et al, 2012 | Resveratrol/red wines | APP/PS1 double transgenic mice with AD | LPS-induced BV2 cells |
In vivo: 350 mg/kg; 15 weeks In vitro: 100 mM; 30 min |
↓: IL-6, M-CSF, MCP-1, MCP-5, CD54, IL-1ra, IL-27, TNF-α, p-Akt, COX-2, iNOS, STAT1, STAT3, TLR4, Iba-1 | TLR4/NF-κB/STAT | (90) |
| Zhou et al, 2019 | ICS II/Epimedium brevicornum Maxim | LPS-induced SD rats | - | In vivo: 3, 10 mg/kg; 7 days | ↓: neuronal changes, neuronal degeneration, GFAP, Iba-1, COX-2, IL-1β, TNF-α, TLR4, MyD88, TRAF6, p-NF-κB ↑: IκB-α degradation |
TLR4/MyD88/NF-κB | (94) |
| Zhang et al, 2021 | DL0410/- | D-gal-induced SD rats | LPS-induced BV2 cells |
In vivo: 1,3, 10 mg/kg-8 weeks In vitro: 1-30 μM-2 h |
↓: MDA,AGEs, SOD1, SOD2, Iba-1, GFAP, TNF-α, IL-1β, IL-6, COX2, iNOS, TLR, MyD88, p-IκBα and NF-κB p65, NF-κB translocationp65, NO, TRAF6, p-IKKα/β, p-IκBα ↑: PSD95, IL-10, claudin-1, claudin-5, occludin, CX43, ZO-1 |
TLR4/MyD88/NF-κB | (97) |
| Zhong et al, 2020 | ATP50-3/Acorus tatarinowii | - | LPS-induced BV2 cells | In vitro: 2.5,5, 10 μM-2 h | ↓: TNF-α, IL-1β, IL-6, COX-2, iNOS, CD11b, TLR4, MyD88, IKKα/β, IκBα, NF-κB p65, PI3K, Akt | TLR4-mediated MyD88/NF-κB and PI3K/Akt | (100) |
| Jing et al, 2019 | DHM/Ampelopsis grossedentata | - | LPS-induced BV2 cells | In vitro: 20, 40, 80, 100 mg/l; 48 h | ↓: TNF-α, IL-1β, IL-6, COX-2, iNOS, p-p65, p-IкBα, TLR4, MyD88 ↑: BV-2 microglia viability |
TLR4/MyD88/NF-κB | (102) |
| Shi et al, 2016 | Gx-50/Sichuan pepper | APP-Tg mice | Aβ42-induced BV2 cells and primary microglia |
In vivo: 1 mg/kg; 2 months In vitro: 1 μM; 30 min |
↓: TNF-α, IL-1β, NO, PGE2, iNOS, COX2, p-IκB, NF-κB translocation, p-ERK1/2, p-p38, p-JNK, TLR4, MyD88, TRAF6 | TLR4-mediated NF-κB and MAPK | (104) |
| Kong et al, 2020 | FTS-B/Forsythiae fructus | APP/PS1 double transgenic mice with AD | LPS-induced BV2 cells |
In vivo: 10, 40 mg/kg; 36 days In vitro: 1, 2.5 μM; 3 h |
↓: Aβ deposition, JIP3, p-JNK/JNK, p-APP/APP, Aβ, TNF-α, IL-1β, IL-6, IL-8, IL-12, ELKS, p-IKK (α+β), p-IκBα, p-NF-κB (Ser536), Iba1, GFAP, NO, iNOS, apoptosis rate of the HT22 cells ↑: TLR3, p-IRF3/IRF3, IFN-β, WDFY1, p-IRF3, cell viability |
WDFY1/TLR3/NF-κB | (108) |
| Lu et al, 2016 | Tan IIA/Salvia miltiorrhiza | Aβ1-42-induced AD rats | - | In vivo: 8 mg/kg; 30 days | ↓: A β, IL-1β, IL-6, GFAP, CD11b, C1q, C3c, C3d | - | (110) |
| Li et al, 2015 | Aβ-induced AD rats | - | In vivo: 50 mg/kg; 15 days | ↓: iNOS, MMP-2, NF-κB p65 | NF-κB | (351) | |
| Maione et al, 2018 | Aβ1-42-induced mice with AD | - | In vivo: 1, 3, 10 mg/kg; 21 days | ↓: GFAP, S100β, COX-2, NF-κB p65 | NF-κB | (112) | |
| Ding et al, 2020 | APP/PS1 double transgenic mice with AD | Aβ1-42-induced BV2 cells |
In vivo: 5, 20 mg/kg; 30 days In vitro: 1, 10 μM; 30 min |
↓: Loss of Syn and PSD-95, Aβ1-40, Aβ1-42, the number of activated microglia, Iba-1, GFAP, TNF-α, IL-6, IL-1β, expression of RAGE, p-IκBα, NF-κB p65 | RAGE/NF-κB | (113) | |
| Jian et al, 2019 | APN/- | 5XFAD mice APN-/-5XFAD mice | AβO-induced BV2 cells | In vitro: 10 μg/ml-2 h | ↓: TNF-α, IL-1β, p-NF-κB p65S536, NF-κB p65, Aβ plaques ↑: p-AMPKT172, GFAP, Iba1 |
AdipoR1-AMPK-NF-κB | (120) |
PL, piperlongumine; BV, bee venom; PUN, punicalagin; TEN, Tenuifolin; D4, a novel piperine derivative; BFE, ethanol extract of BF; BF, Bupleurum falcatum L.; MF, macasiamenene F; MCZ, miconazole; GA, the p65 binding domain of GILZ; GILZ, glucocorticoid induced leucine zipper; K284-6111, 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl) butanamide; EGCG, epigallocatechin-3-gallate; Gen, genistein; SIF, Soybean isoflavone; PTA, protosappanin A; ICS II, icariside II; DHM, dihydromyricetin; FTS-B, forsythoside B; Tan IIA, tanshinone IIA; APN, Adiponectin; p- phosphorylated; AD, Alzheimer's disease; Aβ, amyloid β; APP/PS1, amyloid-β protein/presenilin-1; 5XFAD, 5X familial Alzheimer's disease; AChE, acetylcholinesterase; APN, Adiponectin; AMPK, Adenosine 5′-monophosphate (AMP)-activated protein kinase; BACE1, β-site amyloid precursor protein cleaving enzyme 1; COX-2, cyclooxygenase-2; CHI3L1, chitinase-3 like-protein-1; ERK, extracellular signal-regulated kinases; GFAP, glial fibrillary acidic protein; IKK, IκB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-γ; JNK, c-Jun NH2-terminal kinases; LPS, lipopolysaccha- ride; MyD88, myeloid differentiation factor 88; MAPK, mitogen-activated protein kinase; NLRP3, NOD-like receptor thermal protein domain associated protein 3; NO, nitric oxide; PTA, protosappanin A; PI3K, phosphoinositide 3-kinase; PPARs, peroxisome proliferator-activated receptors; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; TLRs, Toll-like receptors; WDFY1, WD repeat and FYVE domain-containing 1; NF-κB, nuclear factor-kappa-B; Iba-1, ionized calcium binding adaptor molecule 1; STAT3, signal transducers and activators of transcription 3; AP-1, activator protein 1; PGE2, prostaglandin E2.