Table 1.
Summarizes the latest preclinical research findings on the neuroprotective efficacy of dietary small molecules against AD.
| Cell line/animal | Neurotoxin/duration | Drug concentration/duration | Behavioral parameters | Behavioral changes | Mechanism of action | Reference |
|---|---|---|---|---|---|---|
| Chrysin – in vitro studies | ||||||
| SH-SY5Y cells | AlCl3 (50 μM for 24 h) | 50 μM for 24 h | – | – | Oxidative damage ↓ iNOS, IL-1β, and TNFα ↓ Cell death ↓ |
[82] |
| Chrysin – in vivo studies | ||||||
| Swiss mice | AlCl3 (100 mg/kg bw for 90 days) | 10, 30, and 100 mg/kg bw for 90 days | Open-field test, chimney test, and step-down avoidance test | Amelioration of behavioral impairments | SOD, CAT, and GSH ↑ AChE, BChE, and lipid peroxidation ↓ Neuronal degeneration ↓ |
[82] |
| Albino Wistar rats | d-galactose (50 mg/kg bw for 8 weeks) | 20 mg/kg bw for 8 weeks | – | – | SOD, CAT, GPx, GST, GR, G6PD, GSH, vitamins C and E ↑ MDA and protein carbonylation ↓ |
[83] |
| Sprague Dawley rats | d-galactose (50 mg/kg bw for 8 weeks) | 10 and 30 mg/kg bw for 8 weeks | NOL and NOR | Improvement in spatial and recognition memory abilities | Cell proliferation, cell survival, and hippocampal neurogenesis ↑ | [84] |
| C57BL/6 mice | d-galactose (200 mg/kg bw for 8 weeks) | 125 and 250 mg/kg bw for 8 weeks | NOR and Y-maze | Elevation in the percentages of spontaneous alternation, locomotor activity, and spatial learning and memory abilities | AMPK, PGC1α, LKB1, NT-3, NQO1, HO-1, and 5-HT ↑ TNF-α, NF-κB, and GFAP ↓ Neuronal degeneration ↓ |
[85] |
| Albino Wistar rats | Sevoflurane anesthesia for 2 h | 25, 50, and 100 mg/kg bw for 8 weeks | NOL, NOR, MWM, and elevated plus maze | Amelioration of anxiety and explorative behavior and improvements in spatial learning and memory function | Protein and mRNA expression of Nrf2, HO-1, and NQO1 ↑ | [86] |
| Swiss Albino mice | – | 1 or 10 mg/kg bw for 60 days | Open-field test and MWM | Improvements in spatial learning, cognitive function, and motor function | ROS level ↓ SOD, CAT, GPx, and Na+, K+-ATPase activity ↑ BDNF expression ↑ |
[87] |
| C57BL/6 mice | Methimazole (0.1% for 31 days) | 10 or 20 mg/kg bw for 28 days | Open-field test and MWM | Prevention of cognitive dysfunction but no effects on locomotor activity | BDNF and NGF expression ↑ | [88] |
| 7,8-DHF – in vitro studies | ||||||
| SH-SY5Y cells | ΔK280 TauRD-DsRed for 7 days | 5 μM for 7 days | – | – | Tau aggregation, oxidative stress, and caspase-1 activity ↓ Neurite outgrowth, HSPB1, Nrf2, CREB, and Bcl2 ↑ |
[94] |
| PC12 cells | 6-OHDA (100 μM for 24 h) | 1–100 μM for 24 h | – | – | Cell viability, MMP, and SOD ↑ Oxidative injury, MDA, caspase-3, and cell death ↓ |
[95] |
| 7,8-DHF – in vivo studies | ||||||
| Wistar rats | ICV-STZ (3 mg/kg for 3 weeks) | 5, 10, and 20 mg/kg bw for 21 days | NOR and MWM | Recovery of spatial learning and memory function | GSH, SOD, CAT, and GPx ↑ NADPH activity and mitochondrial complexes I, II, III, and IV ↑ MDA, PCO, AChE, p-tau, and neuronal cell death ↓ |
[96] |
| Sprague-Dawley rats | Scopolamine (1 mg/kg for 2 weeks) | 1 mg/kg bw for 4 weeks | MWM | Attenuation of learning and memory deficits | GSH and SOD activities ↑ p-TrkB, p-Akt, and p-Erk ↑ MDA, Aβ40, and Aβ42 levels ↓ |
[97] |
| Tg2576 (Tg) mice and C57BL/6 N mice | – | 5 mg/kg bw for 4 weeks | MWM, elevated plus maze, and open-field test | Improvement in learning and memory abilities | GluA1, GluA2, and AMPA receptor ↑ TrkB, PI3K/Akt, Ras/ERK, and PLCc/CaMKII signaling ↑ |
[98] |
| 5XFAD mice and C57BL/6J mice | – | 5 mg/kg bw for 8 weeks | MWM | Improvement in spatial learning and memory function | TrkB signaling, synapse number, and synaptic plasticity ↑ Aβ deposition and synapse loss ↓ |
[99] |
| 5XFAD mice | – | 5 mg/kg bw for 10 days | Y-maze | Improvement in spatial working memory function | p-TrkB signaling and BDNF ↑ BACE1, C99, and flAPP expression ↓ |
[100] |
| 5XFAD mice | – | 5 mg/kg bw 3 days a week for 8 weeks | – | – | Cortical neurons ↑ Aβ plaque deposition ↓ |
[101] |
| Sprague-Dawley rats | – | 5 mg/kg bw for 28 days | Fear conditioning test | Improvement in memory function | p-TrkB signaling and BDNF ↑ p-CaMKII, p-Erk1/2, p-CREB, and p-GluR1 ↑ Dendritic spines, synapse formation, and synaptic plasticity ↑ |
[102] |
| Wistar rats | Alcohol/HFD (3–15% alcohol in 0.2% saccharin solution) for 12 weeks | 5 mg/kg bw for 28 days | MWM | Attenuation of impaired spatial learning and memory retention | GSH content, Nrf2, and HO-1↑ BDNF expression ↑ MDA, nitrite level, and AChE ↓ Caspase-3, iNOS, IL-1β, and NF-κB expression ↓ |
[103] |
| Naringenin – in vitro studies | ||||||
| PC12 cells | Aβ25-35 (20 μM) for 24 h | 0.4 μM for 24 h | – | – | Cell viability ↑ p-Akt and p-GSK3-β ↑ Cell apoptosis and caspase-3 ↓ |
[111] |
| PC12 cells | H2O2 (100 μM) for 24 h | 25–100 μM for 24 h | – | – | Cell viability ↑ ROS and LDH levels ↓ |
[112] |
| Neuro2a cells | Aβ25-35 (10 μM) for 24 h | 50 μM for 24 h | – | – | Cell viability ↑ p-AMPK, p-ULK1, and LC3II ↑ LDH, SQSTM1, Aβ accumulation ↓ |
[113] |
| BV-2 and N2a cells | LPS (100 ng/mL) for 24 h | 5, 10, and 20 μM for 24 h | – | – | Cell viability ↑ SOCS-3 and PKCδ activation ↑ NO, iNOS, and COX-2 ↓ |
[114] |
| Naringenin – in vivo studies | ||||||
| Swiss mice | LPS (20 mg/kg bw) for 1 day | 10 or 20 mg/kg bw for 3 days | Rotarod | Amelioration of motor impairment | Microglial activation ↓ | [114] |
| Wistar rats | Aβ (4 μL) for 1 day | 100 mg/kg bw for 1 day | Y-maze, radial arm maze, and passive avoidance test | Improvement in spatial learning and memory function | SOD levels ↑ MDA, NO, and neuronal loss ↓ |
[115] |
| ICR mice | Scopolamine (1 mg/kg) for 30 min | 100 mg/kg bw for 1 day | Y-maze and passive avoidance test | Amelioration of spatial learning and memory deficits | AChE levels ↓ | [116] |
| Swiss Albino mice | ICV-STZ (3 mg/kg for 7 days) | 50 mg/kg bw for 14 days | MWM and passive avoidance test | Prevention of spatial learning and cognitive function deficits | 4-HNE, MDA, TBARS, H2O2, and protein carbonyl ↓ GSH, GPx, GR, GST, SOD, and CAT ↑ Na(+)/K(+)-ATPase activity and ChAT-positive neuron ↑ |
[117] |
| Sprague-Dawley rats | ICV-STZ (3 mg/kg bw for 21 days) | 25, 50, and 100 mg/kg bw for 21 days | MWM | Improvement in learning and memory abilities | INS and INSR ↑ p-Tua and p-GSK3-β ↓ | [118] |
| Iron (Fe-dextran) (50 mg/kg) 5 days a week for 4 weeks | 50 mg/kg bw for 28 days | – | – | SOD, CAT, and GPx TBARS, protein carbonyl, and DNA apoptosis ↓ AChE and neuron density loss ↓ |
[119] | |
| Albino Wistar rats | AlCl3 + D-gal (150 mg/kg + 300 mg/kg bw) | 50 mg/kg bw for 14 days | MWM and NOR | Improvement in spatial learning and recognition memory | GSH, SOD, CAT, and GPx ↑ ACh, 5-HT, and DA ↑ Protected neurons ↑ MDA, AChE, and 5-HIAA ↓ |
[120] |
| Albino Wistar rats | LPS (167 μg/kg bw) for 7 days | 25, 50, and 100 mg/kg bw for 7 days | Y-maze, novel object discrimination, passive avoidance test | Amelioration of memory dysfunction | SOD, CAT, GSH, and Nrf2 ↑ NF-κB, TNF-α, TLR4, GFAP, iNOS, and COX2 ↓ |
[121] |
| SAMP8 mice | HFD for 12 weeks | 200 mg/kg bw for 12 weeks | Barnes maze and MWM test | Dramatic improvement in cognitive performance | GSH, SOD, and IL-10 ↑ MDA, NO, TNF-α, and IL-1β ↓ Aβ, APP, BACE1, GFAP ↓ Aβ40, and Aβ42 ↓ p-tau and p-GSK ↓ |
[122] |
| Sprague-Dawley rats | Isoflurane (0.75% for 1 week) | 25, 50 or 100 mg/kg bw for 3 weeks | Y-maze, elevated plus maze, open-field test, and fear conditioning test | Improvement in learning capacity and memory retention and amelioration of cognitive dysfunction | Bcl-xL, Bcl-2, and PI3K/Akt ↑ NF-κB, TNF-α, IL-6, and IL-1β ↓ Caspase-3, Bad, and Bax ↓ |
[123] |
| Luteolin – in vitro studies | ||||||
| PC-12 cells | Aβ25-35 (20 μM/L for 24 h) | 10, 1, 10−1, 10−2, 10−3, 10−4, 10−5, and 10−6 μM/L | – | – | Cell viability and Bcl2 ↑ Bax, caspase-3, p-ERK1/2 and cell death ↓ |
[128] |
| HEK293 and SH-SY5Y cells | Lipofectamine 2000 | 5, 15, and 30 μM for 24 h | – | – | BACE1 and p-NF-κB ↓ APP, C99, and Aβ 1-42 ↓ |
[129] |
| hBMEC and hA cells | fAβ1-42 (20 μM for 72 h) | 3, 10, and 30 μM for 72 h | – | – | Cell viability ↑ ROS levels ↓ TNF-α, IL-6, IL-8, and IL-1β ↓ p-p38, p-Erk1/2, and p-JNK ↓ p-IκB-α and p-NF-κB ↓ |
[130] |
| SH-SY5Y cells | Aβ₁₋₄₂ | Neo and APPsw transfected cells | – | – | Cell viability ↑ ROS levels ↓ SOD and MMP↑ Caspase 3 and caspase-9 ↓ |
[131] |
| SH-SY5Y cells | Zinc (0, 100, 200, 300, or 400 μM) for 1 h | 5–100 μM for 1 h | – | – | CaMKII and p-CaMKII ↑ p-tau at Ser262/356 ↓ | [132] |
| Luteolin – in vivo studies | ||||||
| 3 × Tg-AD and WT, C57BL/6J mice | – | 20 and 40 mg/kg bw for 3 weeks | MWM | Improvement in spatial learning and amelioration of memory deficits | GRP78, IRE1α, and p-p38 ↓ TNF-α, IL-1β, IL-6, and NO ↓ COX-2, iNOS, and p-NF-κB ↓ Aβ-plaque formation ↓ |
[133] |
| APP23 mice | Human APP751 | 100 mg/kg bw for 29 weeks | Y-maze, fear conditioning test, tail suspension test, and forced swimming test | Amelioration of depressive-like behaviors and improvement in spatial learning and memory function | eIF2α, p-eIF2α, and PS1C ↓ IL-1β, Iba-1, and ATF4 ↓ |
[134] |
| Sprague-Dawley rats | STZ (3 mg/kg on the fourth and sixth days) | 10 and 20 mg/kg bw for 1 week | MWM | Amelioration of spatial learning and memory impairment | CA1 pyramidal layer ↑ | [135] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (2 μl for 1 day) | 50, 100, and 200 mg/kg bw for 17 days | MWM and passive avoidance test | Improvement in spatial learning and spatial working memory | SOD level and GSH content ↑ ChAT and Ach content ↑ Bax and Bcl2 ratio ↑ MDA and AChE activity ↓ |
[136] |
| 3 × Tg-AD mice and WT mice | – | 20 or 40 mg/kg bw for 8 weeks | NOR, open-field test, and step-down avoidance test | Recovery of cognitive deficits and amelioration of anxiety, locomotor, and exploration abilities | IDE and UCP2 ↑ SOD level and GSH content ↑ PGC-α, Nrf1, Nrf2, and TFAM ↑ PPARγ, Bcl2, and Mfn2 ↑ APP, BACE1, and Aβ₁₋₄₂ ↓ ROS and MDA ↓ Drp1 and Fis1 ↓ Bax, caspase-3, caspase-9, and cyt-C ↓ |
[137] |
| C57BL/6 N mice | Aβ₁₋₄₂ (5 μl for one day) | 80 mg/kg bw for 2 weeks | – | – | Bcl2, PSD95, and SNAP25 ↑ BACE1 and Aβ₁₋₄₂ ↓ p-p38, p-JNK, Iba-1, and GFAP ↓ TNF-α, IL-1β, and p-NF-κB ↓ Bax, caspase-3, and COX-2 ↓ |
[138] |
| Lycopene – in vitro studies | ||||||
| M146L cells | Aβ-overexpression | 10 μM for 24 h | – | – | Gclc and Gclm expression ↑ Nrf2, p-Akt, p-GSK-3β, and Bcl2 ↑ ROS and MDA levels ↓ APP, BACE1, and caspase-3 ↓ |
[147] |
| SH-SY5Y cells | Aβ₁₋₄₂ (20 μl for 24 h) | 0.2 or 0.5 μM for 24 h | – | – | Cell viability ↑ Bcl2 and MMP ↑ ROS, Bax, p53, and caspase-3 ↓ p-IκBα and p-NF-κB ↓ |
[148] |
| SH-SY5Y cells | RCAN1-overexpressing | 1–2 μM for 24 h | – | – | Cell viability ↑ RCAN1 and MMP ↑ ROS, caspase-3, and cyt-C ↓ p-IκBα and p-NF-κB ↓ |
[149] |
| BV-2 cells | LPS (1 μg/mL 24 h) | 12.5, 25, and 50 μM for 24 h | – | – | Nrf2, HO-1, and NQO-1 ↑ ROS levels ↓ Iba-1 and COX-2 ↓ p-p38, p-Erk, p-JNK, and p-Akt ↓ p-IκB-α and p-NF-κB ↓ |
[150] |
| Primary culture | t-BHP (2 μM for 24 h) | 0.1–16 μM for 24 h | – | – | Cell viability ↑ NGF, VEGF, and BDNF ↑ Bcl2 and MMP ↑ SYP and PSD95 ↑ p-PI3K and p-Akt ↑ ROS, Bax, caspase-3, and cyt-C ↓ |
[151] |
| Primary culture | Aβ25–35 (25 μM for 24 h) | 0.1–10 μM for 24 h | – | – | Cell viability ↑ Bcl2 and MMP ↑ ROS, Bax, and caspase-3 ↓ |
[152] |
| Primary culture | Aβ25–35 (10 μM for 24 h) | 0.1–5 μM for 24 h | – | – | Mitochondrial complex I, II, III, and IV activity and ATP content ↑ Mito Tfam levels and Mito-cyt-C ↑ mtDNA copy numbers ↑ mtDNA transcript levels ↑ 8-OHdG and cytosolic-C ↓ Intracellular ROS level ↓ Mitochondrial ROS level ↓ |
[153] |
| Lycopene-in vivo studies | ||||||
| Sprague-Dawley rats | Aβ₁₋₄₂ (3 μl for one day) | 2.5 or 5 mg/kg bw for 3 weeks | MWM | Improvement in spatial learning performance and alteration in locomotor activity | Mitochondrial complex I, II, III, and IV activity and BDNF ↑ CAT, SOD, and GSH ↑ NO, MDA, and LPO levels ↓ AChE, TNF-α, and IL-6 ↓ Caspase-3 activity ↓ |
[154] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (10 μl for one day) | 1, 2, and 4 mg/kg bw for 3 weeks | MWM, elevated plus maze, and actophotometer test | Attenuation of poor latency performance and improvement in learning and memory performance | Mitochondrial complex I, II, III, and IV activity ↑ CAT, SOD, and GSH ↑ NO, MDA, and LPO levels ↓ AChE, TNF-α, TGF-β1, and IL-6 ↓ Caspase-3 activity ↓ |
[155] |
| APP/PS1 mice and WT C57/BL6J mice | – | 4 mg/kg bw | MWM | Amelioration of spatial learning and memory impairments | CD105, VEGF, and NeuN ↑ p-Akt, LXRα, and LXRβ ↑ Aβ aggregation, GFAP, and iNOS ↓ |
[156] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (3 μl for 1 day) | 5 mg/kg bw for 3 weeks | MWM | Improvement in spatial learning and cognitive function | TNF-α, IL-1β, and IL-6 ↓ TLR4 and p-NF-κB ↓ APP and PS1 ↓ |
[157] |
| C57BL/6J mice | LPS (0.25 mg/kg bw for 9 days) | 30 mg/kg bw for 5 weeks | MWM and Y-maze test | Prevention of losses in spatial learning and memory | IL10 and MMP3 ↑ GSH, CAT, and SOD ↑ APP and BACE1 ↓ iNOS, COX-2, IL-6, and MMP9 ↓ Aβ aggregation ↓ Iba-1 activation ↓ |
[150] |
| Albino Wistar rats | Fructose (10% for 16 weeks) | 4 mg/kg bw for 10 weeks | MWM | Recovery of impaired learning and memory | IR, IGF-1R, PI3K, and p-Akt ↑ SOD, CAT, GPx, and GSH ↑ PPARγ expression ↑ ROS, AChE, LPO, and PCC ↓ TNF-α, IL-1β, and p-NF-κB ↓ |
[158] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (10 μl for 14 days) | 5 mg/kg bw for 5 weeks | MWM | Mitigation of spatial memory and learning dysfunction | IL-10 and TGF-β1 levels ↑ Aβ accumulation ↓ TNF-α and IL-1β levels ↓ TLR4 and p-NF-κB ↓ |
[159] |
| Ferulic acid – in vitro studies | ||||||
| PC12 cells | LPS (1 μg/mL for 24 h) | 2.5, 5, 10, 20 and 40 μM for 24 h | – | – | CREB, p-CREB, and PDE4 ↑ TNF-α, IL-1β, and IL-6 ↓ |
[164] |
| SH-SY5Y cells | Aβ₁₋₄₂ (20 μl for 72 h) | 10–50 μM for 72 h | – | – | Aβ42 aggregation ↓ | [165] |
| SH-SY5Y cells | Aβ₁₋₄₂ (5 μl for 24 h) | 1–50 μM for 24 h | – | – | Cell viability ↑ Aβ42 aggregation ↓ Intracellular ROS formation ↓ Mitochondrial ROS formation ↓ Repair of membrane damage ↓ |
[166] |
| BV-2 cells | LPS (100 ng/mL for 24 h) | 2.5, 7.5, and 22.5 μM for 24 h | – | – | Cell viability ↑ PGE2, IL-1β, and NO ↓ iNOS, COX-2, and TLR4 ↓ |
[167] |
| BV-2 cells | LPS (1 μg/mL for 12 h) | 55 μM for 24 h | – | – |
p-AMPK, p-ULK1, and Beclin1 ↑ LC3, LAMP2A, and TFEB ↑ IL-6, IL-1β, TNF-α, and p-65 ↓ |
[168] |
| Ferulic acid – in vivo studies | ||||||
| ICR mice | Trimethyltin chloride (2.5 mg/kg bw for one day) | 20 or 50 mg/kg bw for 4 weeks | Y-maze and passive avoidance test | Attenuation of memory impairment and behavioral disabilities | ChAT activity ↑ | [169] |
| Male APP/PSI mice | – | 50 mg/kg bw for 4 months | MWM, Open-field test, NOR, and fear conditioning test | Recovery of impaired learning and memory | PSD95 and Syn1 ↑ APP and APPβ ↓ Neuronal loss ↓ BACE-1 and PS1 ↓ |
[170] |
| APP/PS1 transgenic mice and C57 mice | – | 20 mg/kg bw for 30 days | MWM | Reduction in spatial memory deficits | Cerebral blood flow ↑ Aβ plaque deposition ↓ APP, BACE1, and p-NF-κB ↓ |
[171] |
| PSAPP transgenic mice and WT mice | – | 30 mg/kg bw for 90 days | Y-maze, NOR, and radial arm water maze test | Recovery of episodic memory, spatial working memory, and spatial reference learning and memory deficits | Synaptophysin ↑ Oxidative stress ↓ Aβ deposits ↓ C99 and BACE1 ↓ IL-1β, TNF-α, Iba-1 and GFAP ↓ |
[172] |
| APP/PS1 mice | – | 5.3 or 16 mg/kg bw for 6 months | Y-maze test and NOR | Enhancement of behavioral performance and memory function | Aβ1–42 deposits ↓ Aβ1–40 deposits ↓ IL-1β levels ↓ |
[173] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (10 μl for 7 days) | 50, 100, and 250 mg/kg bw for 3 weeks | – | – | PKB and p-PKB ↑ IL-1β and GFAP activation ↓ p-p38 and p-ERK1/2 expression ↓ Caspase-3 and FasL expression ↓ |
[174] |
| Transgenic C. elegans | Aβ₁₋₄₂ over-expression | 1, 10, and 100 μM for 24–96 h (different assays at different time points) | – | – | HLH-30 activation ↑ Aβ monomers, oligomers, and deposits ↓ PolyQ40 aggregation ↓ |
[175] |
| Ellagic acid – in vitro studies | ||||||
| SH-SY5Y cells | Aβ₁₋₄₂ (10 μl for 12 h) | 100–300 μM for 24 h | – | – | Cell viability ↑ Morphology of Aβ42 aggregates ↓ Aβ oligomer levels ↓ |
[179] |
| PC-12 cells | H2O2 (40 μM) and Aβ25-35 (0.01 μM) for 24 h | 0.5–5.0 μg/ml for 24 h | – | – | Cell viability ↑ Intracellular ROS ↓ calcium ion influx ↓ |
[180] |
| SH-SY5Y cells | d-galactose (200 mM for 24 h) | 0.01–10 μM for 24 h | – | – | Cell viability ↑ GSH content ↑ MDA and ROS formation ↓ β-GAL, AGEs, and TNF-α level ↓ |
[181] |
| BV-2 cells | LPS (1 μg/mL for 24 h) | 25, 50, and 100 μM for 24 h | – | – | p-p38 and p-ERK1/2 expression ↓ TNF-α and NO activity ↓ |
[182] |
| Ellagic acid – in vivo studies | ||||||
| APP/PS1 double-transgenic and WT-C57BL/6 mice | – | 50 mg/kg bw for 2 months | MWM | Improvement in learning and memory performance | Aβ₁₋₄₂ deposits ↓ BACE1, APP and pThr668-APP ↓ pSer199-tau and pSer396-tau ↓ pTyr216-GSK3β activation ↓ Percentage of apoptotic cells ↓ Caspase-3 expression ↓ |
[183] |
| Sprague-Dawley rats | STZ (3 mg/kg for 1 day) | 25 and 50 mg/kg bw for 5 weeks | Y-maze and radial arm maze test | Improvement in memory score and cognitive performance | CAT and GSH content ↑ Synaptophysin ↑ MDA, CRP, and AChE activity ↓ GFAP and Aβ-plaques ↓ |
[184] |
| Sprague-Dawley rats | AlCl3 (50 mg/kg for 4 weeks) | 50 mg/kg bw for 4 weeks | NOR | Improvement in episodic memory | SOD and GSH content ↑ TBARS activity ↓ Neuronal loss ↓ NFTs and NPs ↓ APP and caspase-3 expression ↓ |
[185] |
| Sprague-Dawley rats | Aβ₁₋₄₂ (10 μg/kg for one day) | 10, 50, and 100 mg/kg bw for 7 days | Y-maze, radial arm maze test, NOR, and passive avoidance test | Prevention of learning and memory deficits | CAT, GSH, and Nrf2 ↑ MDA, NO, AChE, and BChE ↓ TLR4 and NF-κB ↓ CA1 neuronal loss ↓ |
[186] |
| Sprague-Dawley rats | Scopolamine (2 mg/kg for 1 day) | 25, 50, and 100 mg/kg bw for 3 weeks | MWM and passive avoidance test | Attenuation of learning and memory deficits | CAT and SOD ↑ MDA content ↓ |
[187] |
| Caffeic acid – in vitro studies | ||||||
| PC12 cells | Aβ1–42 (10 μl for 24 h) | 10 or 20 μg/mL for 24 h | – | – | Cell viability ↑ Calcium levels ↓ AT8 and phosphorylation of tau ↓ Phosphorylation of GSK-3β ↓ |
[194] |
| HT22 cells | Acrolein (25 μl for 24 h) | 5–50 μM for 24 h | – | – | Cell viability ↑ GSH levels and MMP ↑ ADAM-10, p-Akt, and LR-11 ↑ p-Erk and p-GSK-3β ↑ Intracellular ROS production ↓ p-p38 and p-JNK1 ↓ RAGE and BACE1 ↓ |
[195] |
| Caffeic acid – in vivo studies | ||||||
| Sprague-Dawley rats | HFD for 30 weeks | 200 mg/kg bw for 12 weeks | MWM | Amelioration of learning and memory impairments | SOD and CAT levels ↑ p-GSK-3β and synaptophysin ↑ GSSG activity ↓ APP and BACE1 ↓ Aβ₁₋₄₂, PSD95, and drebrin ↓ p-tau (Ser 396), p-tau (Ser 404), and p-tau (Thr 181) ↓ |
[196] |
| Sprague-Dawley rats | Aβ1–40 (5 μl for 1 day) | 100 mg/kg bw for 2 weeks | MWM | Prevention of learning deficits and increased cognitive function | GSH and CAT levels ↑ AChE activity and NO level ↓ IL-6 and TNF-α activities ↓ p53, p-p38, and p-NF-κB-p65 ↓ Caspase 3 protein expression ↓ |
[197] |
| Sprague-Dawley rats | ICV-STZ (3 mg/kg for 1 and 3 days) | 10, 20, and 40 mg/kg bw for 3 weeks | MWM, object recognition test, and spontaneous locomotor activity | Improvement in discriminating ability and alleviation of spatial learning and memory deficits | GSH levels ↑ AChE activity and NO level ↓ MDA content and protein carbonyl ↓ |
[198] |
| C57BL/6 mice | Aβ1–40 (5 μl for one day) | 50 mg/kg bw for 2 weeks | MWM and Y-maze | Improvement in spatial working memory and cognitive performance | Nrf2 and HO-1 expression ↑ p-PI3K and BDNF expression ↑ SYN, SNAP-23, and SNAP-23 ↑ PSD-95 expression ↑ BACE1 and Aβ₁₋₄₂ deposits ↓ GFAP and Iba-1 expression ↓ IL-1β, TNF-α, and p-NF-κB-p65 ↓ |
[199] |
| ApoE−/− mice and WT-C57BL/6J | – | 20 mg/kg bw for 8 weeks | MWM and Y-maze | Amelioration of cognitive decline and spatial memory impairment | ABCA1 and ABCG1 ↑ Aβ accumulation ↓ TNF-α, IL-6, and MCP-1 ↓ |
[200] |
| Gallic acid – in vitro studies | ||||||
| Neuro-2A cells and BV-2 cells | Aβ1–40 (5 μl for 24 h) | 5, 25, and 50 μM for 24 h | – | – | Cell viability ↑ IL-1β and TNF-α expression ↓ COX-2 and iNOS expression ↓ p-NF-κB-p65 expression ↓ |
[204] |
| Gallic acid – in vivo studies | ||||||
| ICR mice | Aβ1–40 (5 μl for 7 days) | 10 or 30 mg/kg bw for 4 weeks | Y-maze and passive avoidance test | Restoration of memory deficits and cognitive function | IL-1β and TNF-α expression ↓ COX-2 and iNOS expression ↓ p-NF-κB-p65 expression ↓ |
[204] |
| APP/PS1 and WT-C57BL/6 N mice | – | 30 mg/kg bw for 4 weeks | MWM, NOR, and Y-maze | Mitigation of spatial learning and reference memory deficits | PSD-95 expression ↑ GFAP and Iba-1 expression ↓ Aβ accumulation ↓ |
[205] |
| APP/PS1 mice | – | 20 mg/kg bw for 6 months | Y-maze, radial arm maze test, and NOR | Attenuation of spatial learning and working memory impairment and reversal of episodic memory impairment | APP, C99, and BACE1 ↓ GFAP and Iba-1 expression ↓ Aβ deposition |
[206] |
| Sprague-Dawley rats | AlCl3 (200 mg/kg bw for 60 days) | 100 or 200 mg/kg bw for 8 weeks | Y-maze and MWM | Improvement in learning and memory status | SOD, CAT, and GSH content ↑ Na+, Ca2+, and Zn2+ ↑ Dopamine and serotonin ↑ Norepinephrine ↓ K+ and CU2+ ↓ H2O2, MDA, and NO levels ↓ NFTs and NPs ↓ |
[207] |
| Sprague-Dawley rats | ICV-STZ (3 mg/kg bw for 1 and 3 days) | 100 or 200 mg/kg bw for 26 days | MWM and passive avoidance test | Mitigation of spatial learning and memory impairment | SOD, CAT, and GPx content ↑ MDA levels ↓ |
[208] |
| Sprague-Dawley rats | Sodium arsenite (2.5 mg/kg for 28 days) | 50 or 100 mg/kg bw for 4 weeks | MWM, elevated plus maze, forced swim test, and light-dark activity box test | Attenuation of anxiety-like behavior and improvement in learning and memory performance | SOD, CAT, and GPx content ↑ AChE activity and MDA levels ↓ |
[209] |
| Sprague-Dawley rats | Aβ1–40 (1 μg/1 μL for 1 day) | 50, 100, and 200 mg/kg bw for 10 days | – | – | Aβ accumulation ↓ | [210] |
| Epigallocatechin-3-gallate – in vitro studies | ||||||
| BV2-cells | Aβ25₋35 (25 μM for 24 h) | 2, 5, and 10 μM for 24 h | – | – | Cell viability ↑ Bcl2 and GSH levels ↑ MDA and ROS production ↓ iNOS and NO production ↓ Bax expression ↓ |
[218] |
| U373MG cells | Aβ25–35 (30 μM for 24 h) and IL-1β (10 ng/mL for 24 h) | 0.2–200 μM for 24 h | – | – | Cell viability ↑ MKP-1 expression ↑ IL-6, IL-8, and VEGF ↓ PGE2, COX-2, and p-NF-κB-p65 ↓ p-p38 and p-JNK ↓ |
[219] |
| BV2-cells | LPS (1 μg/mL for 1 h) | 0–350 μM for 24 h | – | – | Cell viability ↑ IL-6, TNF-α, and NO production ↓ MIF, CCL2, and TNFS10 ↓ STAT1, TRAF2, and TRAF3 ↓ TRAF5 and NFKΒ2 ↓ AKT3, mTOR, and NF-κB2 |
[220] |
| SH-SY5Y cell and BV-2 cells | Aβ1–40 (10 μM for 6 h) and LPS (1 μg/mL for 1 h) | 10 μM for 24 h | – | – | Cell viability ↑ IL-1β, IL-18, and Iba-1 expression ↓ Aβ accumulation ↓ Caspase-1 and caspase-1 p20 ↓ Caspase-11 p26 and NLRP3 ↓ p-NF-κB-p65, p-I κB-α, and TLR4 ↓ |
[221] |
| Epigallocatechin-3-gallate – in vivo studies | ||||||
| APP/PS1 mice and WT mice | – | 2 mg/kg bw for 28 days | – | – | IL-1β, IL-18, and Iba-1 expression ↓ Aβ accumulation ↓ Caspase-1 and Caspase-1 p20 ↓ Caspase-11 p26 and NLRP3 ↓ p-NF-κB-p65, p-I κB-α, and TLR4 ↓ |
[221] |
| APP/PS1 mice and WT mice | – | 50 mg/kg bw for 8 weeks | MWM and NOR | Alleviation of memory and cognitive deficits | Synapsin-1 and synaptophysin ↑ Synaptotagmin and PSD93 ↑ PSD95, MAP-2, and GluR1 ↑ IL-4, IL-10, and IL-13 ↑ Aβ accumulation ↓ Tau phosphorylation ↓ Iba-1, IL-6, TNF-α, and IL-1β ↓ |
[222] |
| Sprague-Dawley rats | Aβ1–40 (1 nM/μL for 1 day) | 100, 250, and 625 mg/kg bw for 8 weeks | MWM | Improvement in learning and memory function | Ach, GPx and SOD content ↑ Tau aggregation ↓ Tau phosphorylation and BACE1 ↓ Aβ1–42 expression ↓ MDA and AChE ↓ |
[223] |
| ICR mice | LPS (0.250 mg/kg bw for 7 days) | 15 or 3 mg/kg bw for 4 weeks | MWM | Amelioration of memory impairment and cognitive dysfunction | Aβ accumulation ↓ APP, C99, and BACE1 ↓ iNOS and COX-2 expression ↓ IL-1β, TNF-α, and IL-16 ↓ GFAP and caspase-3 expression ↓ |
[224] |
| APP/PS1 mice and WT mice | HFD for 12 weeks | 40 mg/kg bw for 12 weeks | MWM and NOR | Improvement in spatial learning and memory function | ADAM10, p-CDK5, and pAKT ↑ GSK3β and pGSK3β, and p-CREB ↑ APP and BACE1 ↓ GFAP, ATF4, and CHOP ↓ p-JNK, p-ERK, and TRL4 ↓ IRE1/p-IRE1 and ATF6 ↓ |
[225] |
| C57BL/6 mice | HFD for 8 weeks | 5, 15, and 45 mg/kg bw for 8 weeks | Barnes maze and NOR | Improvement in cognitive function and amelioration of cognitive decline | Prevotella ↑ Gut function and diversity ↑ Bifidobacteriales ↓ |
[226] |
| Theaflavins – in vivo studies | ||||||
| ICR mice | d-galactose (120 mg/kg bw for 56 days) | 15, 30, and 60 mg/kg bw for 8 weeks | Y-maze and NOR | Alleviation of memory and cognitive deficits |
Ach and ChAT activity ↑ SOD, GSH, GS, and GLS ↑ Nrf2, Prx2, GSH-px1, and SOD 1 ↑ MDA, GLU, and AChE activity ↓ |
[231] |
| C57BL/6J mice | LPS (10 μg for 1 h) | 10 or 50 mg/kg bw for 3 days | Y-maze and tail suspension test | Attenuation of concomitant cognitive impairment and Alzheimer-like behavior |
Dendritic spine density ↑ MIP-1α- and TNF-α ↓ |
[232] |
| Vanillin – in vitro studies | ||||||
| PC12 cells | Aβ1–40 (20 μM for 12 h) | 0, 10, 30, and 100 μM for 24 h | – | – | Cell viability ↑ SOD, CAT, and GSH ↑ MMP and Bcl2 ↑ LDH leakage ↓ MDA and ROS production ↓ Caspase-3, Bax, and apoptosis ↓ |
[237] |
| BV2-cells | LPS (200 ng/mL for 24 h) | 0–400 μM for 24 h | – | – | Cell viability ↑ iNOS and COX-2 expression ↓ IL-1β, TNF-α, and IL-16 ↓ p-p38, p-JNK, and p-ERK ↓ p-NF-κB-p65, and p-I κB-α ↓ |
[238] |
| Vanillin-in vivo studies | ||||||
| Swiss Albino mice | Scopolamine (2 mg/kg bw for 10 days) | 10 or 20 mg/kg bw for 10 days | Passive avoidance, elevated plus maze, and MWM | Reversal of memory and behavioral deficits |
GSH and CAT ↑ AChE and TBARS ↓ IL-6 and TNF-α ↓ |
[239] |
| Swiss Albino mice | AlCl3 (5 mg/kg for 90 days) and d-galactose (60 mg/kg bw for 90 days) | 40 mg/kg bw for 3 months | NOR, elevated plus maze, and MWM | Mitigation of memory and behavioral deficits |
GSH and CAT ↑ BDNF and neuron density ↑ AChE and TBARS ↓ BACE1 and caspase-3 ↓ Aβ accumulation ↓ |
[240] |
| ICR mice | Scopolamine (1 mg/kg bw for 28 days) | 40 mg/kg bw for 4 weeks | Passive avoidance and MWM | Attenuation of spatial learning impairment and cognitive dysfunction | ID-1 protein expression ↑ ID-1-immunoreactive cells ↑ NeuN-immunoreactive neurons ↑ DCX-immunoreactive cells ↑ Ki-76-immunoreactive cells ↑ |
[241,242] |