Table 1.
Characteristics of studies inserted in the review.
| Authors, year, country | Substance(s) | Disease | Animals, (strain/sex) n (per group) | Doses, route, administration, period | Preclinical models | Evaluated parameters | |
|---|---|---|---|---|---|---|---|
| Behavior | Biochemical/molecular | ||||||
| Wei et al., 2013 [36], China | (2S)-5, 2′, 5′-trihydroxy-7-methoxyflavanone (TMF) | Alzheimer's | Mice (Kunming/NR) (n = 8) | 4 or 8 mg/kg, i.p., 1 week | D-galactose | (i) Spatial learning and memory (Morris water maze test) | (i) Colorimetric assay: GSH and GSSG (ii) ELISA: AP-1 and BDNF (iii) Western blot: CREB and p-CREB |
| Mani et al., 2013 [37], India | Naringin | Alzheimer's | Rats (W/M), n = 6 | 100 mg/kg, p.o., 21 days | Deltamethrin | (i) NR | (i) Agarose gel electrophoresis: DNA fragmentation (ii) Biochemical: LDH, CK, AChE, SOD, CAT, GPx, GR, GSH, vitamin C, vitamin E, and lipid peroxidation level (iii) Histological analysis (iv) Native gel electrophoresis: SOD and CAT |
| Nakajima et al., 2013 [38], Japan | Nobiletin | Alzheimer's | Rats (SAMP8/M) n = 47 | 10 or 50 mg/kg, i.p., unclear | Senescence-accelerated prone mouse (SAMP8) model | (i) Nonspatial memory (novel object test) (ii) Contextual and auditory fear memory (fear conditioning test) (iii) Emotional reactivity, anxiety (elevated plus maze test) |
(i) Biochemical: MDA, protein carbonyl level, SOD, and GPx (ii) HPLC: GSH and GSSG (iii) Real-time RT-PCR: GPx1 and GPx4 (iv) Western blot: Aβ1–42, tau, p-tau, GPx1, and GPx4 |
| Moghbelinejad et al., 2014 [39], Iran | Rutin | Alzheimer's | Rats (W/M) n = 30 | 100 mg/kg, i.p., 3 weeks | Amyloid beta (Aβ1–42) | (i) Memory retrieval (passive avoidance apparatus test) | (i) Biochemical: MDA and total SH groups (ii) Real-time RT-PCR: BDNF, ERK1, ERK2, and CREB1 |
| Li et al., 2014 [40], Germany | Hesperidin | Alzheimer's | Mice (APP/PS1–21/M), n = 12 | 100 mg/kg, p.o., NR | Transgenic APP/PS1–21 mouse model | (ii) Nesting behavior (nest building assay) (iii) Social behavior, degree of interaction (social interaction assay) |
(i) Double immunostaining (ii) Immunohistochemistry: Aβ, GFAP, TGF-β1, and Alzheimer precursor protein A4 |
| Javed et al., 2014 [41], India | Hesperidin | Alzheimer's | Mice (S/M), n = 10 or n = 12 | 100 and 200 mg/kg, i.p, 15 days | Streptozotocin | (i) Spatial learning and memory (Morris water maze test) | (i) Biochemical: TBARS, GSH, AChE, ganglioside, and phospholipids (ii) Immunohistochemistry: GFAP, NF-κB, iNOS, and COX-2 |
| Walker et al., 2015 [42], USA | Epigallocatechin gallate | Alzheimer's | Mice (TgCRND8 (Tg) and wild type (nTg)/M and F), n = 10, n = 11, or n = 12 | 50 mg/kg, p.o., 4 months | TgCRND8 amyloid precursor protein transgenic mice | (i) Acquisition experience (nest building) (ii) Locomotor activity and exploratory (open field test) (iii) Novelty-seeking and anxiety-like behaviors (light-dark box) (iii) Learning (Barnes maze) |
(i) ELISA: Aβ1–42 |
| Kou et al., 2016 [43], China | Dihydromyricetin | Alzheimer's | Rats (SD/M), n = 10 | 100 and 200 mg/kg, p.o., 6 weeks | D-galactose | (i) Spatial learning and memory (Morris water maze test) | (i) Histological analysis (ii) Real-time PCR: miR-34a (iii) SA-β-gal staining (iv) Western blot: caspase-3, Bcl-2, SIRT1, p53, p21, Atg7, LC3-II/LC3-I, GFAP, and mTOR |
| Ali et al., 2016 [44], Republic of Korea | Anthocyanins and anthocyanin-loadedPEG-AuNPs | Alzheimer's | Mice (C57BL/M), n = 15 | 12 μg/g/day, p.o., 14 days | Amyloid beta (Aβ1–42) | (i) Spatial learning and memory (Morris water maze and Y-maze tests) | (i) Immunohistochemical Nissl and FJB staining (ii) Immunofluorescence (iii) Western blot: Aβ, BACE-1, SNAP23, synaptophysin, p-AMPARs, p-PI3K, p-Akt, p-GSK3β, p-tau, PSD95, caspase-3, Cyt c, Bax, Bcl2, and poly (ADP-ribose) polymerase-(PARP-1) |
| Ramalingayya et al., 2016 [45], India | Naringin and Rutin | Alzheimer's | Rats (W/F), n = 12 | 50 and 100 mg/kg, p.o., 15 days | Donepezil and scopolamine | (i) Locomotor activity and time spent in the center zone (open field test) (ii) Nonspatial memory (object recognition task) |
(i) Hematological |
| Chen et al., 2016 [46], China | Quercetin | Alzheimer's | Mice (C57BL/6J/M), NR | 30 mg/kg, p.o., NR | Cognitive disorders per high-fat diet (HFD) | (i) Spatial learning and memory (Morris water maze test) | (i) Immunohistochemisty: p-PERK, p-IRE1α, NLRP3, and p-tau (ii) Light microscopy: CA1 (iii) Western blot: AMPK, p-AMPK, IRE1α, p-IRE1α, eIF-2α, p-IF-2α, TXNIP, NLRP3, GSK-3β, p-GSK-3βser9, tau, and p-tau |
| Song et al., 2017 [47], China | Silibinin | Alzheimer's | Rats (SD/M), NR | 25, 50, and 100 mg/kg, p.o., 28 days | Amyloid beta (Aβ25–35) | (i) Anxiety and locomotor activity (Elevated plus maze test) (ii) Spatial learning and memory ability (Morris water maze test) (iii) Learning and memory (novel object-recognition test) (iv) Memory (memory flexibility test) |
(i) Biochemical: MDA and GSH (ii) ELISA: IL-1β, IL-4 (iii) Flow cytometric analysis (iv) Transmission electron microscopy (v) Western blot: NF-κB, COX-2, iNOS, p53, and p-p53 |
| Moreno et al., 2017 [48], Spain | Quercetin and quercetin-loadednanoparticles | Alzheimer's | Rats (SAMP8/M), n = 8 | Quercetin (25 mg/kg, p.o., 2 months) Quercetin-loaded nanoparticles (25 mg/kg every 48 hours, p.o., 2 months) |
Senescence-accelerated prone mouse (SAMP8) model | (i) Locomotor activity (open field test) (ii) Motor coordination and balance (rotarod test) (ii) Exploratory motivation (marble burying test) (iii) Spatial memory and both the working and reference memory functions (Morris water maze test) |
(i) Western blot: GFAP and CD11b |
| Godoy et al., 2016 [49], Chile | Quercetin | Alzheimer's | Rats (B6.129S7-Sod2tm1Leb/J/NR), NR | 50 mg/kg, two times a week, p.o., 4 weeks | Amyloid beta (Aβ25–35) | (i) NR | (i) Electrophysiology |
| Palle and Neerati, 2016 [50], India | Quercetin and quercetin nanoparticles | Alzheimer's | Rats (W/M), n = 6 | 30 mg/kg, i.p., 8 days | Scopolamine | (i) Conditioning, avoidance responses (conditioned avoidance test) (ii) Learning, memory (rectangular maze test) |
(i) Biochemical: MDA, GPx, AChE, and CAT (ii) Histological analysis |
| Ahmad et al., 2016 [51], Republic of Korea | Fisetin | Alzheimer's | Mice (C57BL/6N/M), n = 12 | 20 mg/kg, i.p., 2 weeks | Amyloid beta Aβ1–42 | (i) Spatial memory and both the working and reference memory functions (Morris water maze test) | (i) FJB staining (ii) Immunofluorescence: Aβ (B4), synaptophysin, PSD95, p-tau, GFAP, and Iba-1 (iii) Immunohistochemistry: caspase-3 (iv) Western blot: caspase-9, SYN, p-AMPAR1, p-CREB, p-CAMKII, p-PI3K, and p-Akt |
| Rehman et al., 2017 [52], Republic of Korea | Anthocyanins | Alzheimer's | Rats (SD/M), n = 13 | 100 mg/kg, i.p., 7 weeks | D-galactose | (i) Spatial learning and memory (Morris water maze and Y-maze tests) | (i) Biochemical: ROS, MDA (ii) Immunofluorescence: Aβ, 8-OxoG, p-JNK, GFAP, and Iba-1 (iii) Western blot: Aβ, BACE-1, RAGE, 8-OxoG, TNF-α, iNOS, p-JNK, Bax, Bcl2, PARP-1, syntaxin, synaptophysin, SNAP-23, p-CREB, GFAP, and Iba-1 |
| Kim et al., 2017 [53], Republic of Korea | Anthocyanins alone and anthocyanin-loaded poly (ethylene glycol) gold nanoparticles (PEG-AuNPs) | Alzheimer's | Mice (C57BL/6N/M), n = 8 | 10 mg/kg, i.v., 14 days | Amyloid β (Aβ1–42) | (i) NR | (i) ICP-AES (ii) Immunofluorescence: GFAP, Iba-1, and RAGE (iii) Nissl staining (iv) TEM (v) Western blot: Aβ, BACE-1, GSK3β, CDK5, tau, NF-κB, iNOS, p-JNK, Bcl2, Bax, Cyt c, FJB, COX-2, NOS3, IL-1β, and TNF-α |
| Sharma et al., 2016 [54], India | Quercetin | Alzheimer's and Parkinson's | Rats (W/M), n = 6 | 10 mg/kg, p.o., 12 weeks | Aluminum | (i) NR | (i) Biochemical: ROS, MnSOD (ii) DNA isolation for DNA fragmentation (iii) Electron microscopy analysis (iv) Histological analysis (v) Immunohistochemistry: MnSOD, c-c, and caspase-3 (vi) RT-PCR: MnSOD; (vi) Western blot: MnSOD, Cyt c, Bax, Bcl-2, p53, and caspase-3 |
| Jeong et al., 2015 [55], Republic of Korea | Naringin | Epilepsy, Parkinson's, and Alzheimer's | Mice (C57BL/6/M) NR | 80 mg/kg, i.p., 7 days | Kainic acid | (i) NR | (i) Immunohistochemical: NeuN and Iba-1 (ii) Light microscopy: CA1 (iii) Western blot: LC3B and TNFα |
| Lee et al., 2014 [56], Republic of Korea | Baicalein | Parkinson's | Mice (C57B/6/M), n = 8–14 | 1 and 10 mg/kg (i.p.), 7 days | MPTP | (i) Motor coordination and balance (rotarod test) | (i) DAB immunostaining: TH (ii) Double label immunostaining: TH, GFAP, and Iba-1 (iii) Histological analysis (iv) Western blot: GFAP |
| Antunes et al., 2014 [57], Brazil | Hesperidin | Parkinson's | Mice (C57 BL/6/F), n = 10 | 50 mg/kg, p.o., 28 days | 6-OHDA | (i) Depression (Tail-suspension test) (ii) Spatial learning and memory (Morris water maze) (iii) Locomotor activity and time spent in the center zone (open field test) |
(i) Biochemical: GSH, ROS, TRAP, SOD, CAT, GR, GPx, GST, DA, DOPAC, and HVA |
| Lou et al., 2014 [58], China | Naringenin | Parkinson's | Mice (C57BL/6/F), n = 10 | 70 mg/kg, p.o., 4 days | 6-OHDA | (i) Rotational behavior—numbers of rotations (apomorphine-induced circling behavior) | (i) HPLC-MS: DA, DOPAC, and HVA (ii) Immunohistochemistry: TH (iii) Western blot: Nrf2, HO-1, GCLM, GCLC, Lamin A, cleaved caspase-3, p-JNK, JNK, p-p38, and p38 |
| Wang et al., 2015 [59], China | Tanshinone I | Parkinson's | Mice (C57BL/6/M), NR | 5, 10 mg/kg, p.o., 7 days | MPTP | (i) Motor coordination and balance (rotarod test) | (i) Biochemical: ALT, AST, and ALP (ii) ELISA: TNF-α and IL-10 (iii) HPLC: DA, DOPAC, HVA, and MPP+ (iv) Immunohistochemistry: TH and Iba-1 |
| Chen et al., 2015 [60], China | Silibilin | Parkinson's | Rats (M and F), NR | 25 and 50 mg/kg, p.o. in second day | Increased neonatal iron intake | (i) Locomotor activity and time spent in the center zone (open field test) (ii) Motor coordination and balance (rotarod test) |
(i) Biochemical: MDA and GSH (ii) HPLC-ECD: DA and 5-HT |
| Mu et al., 2016 [61], China | Quercetin | Parkinson's | Rats (SD/M), NR | 100, 200, and 400 mg/kg, i.g., NR | 6-OHDA | (i) Rotational behavior—numbers of rotations (apomorphine-induced circling behavior) | (i) HPLC-ECD: DA, DOPAC, HVA, 5-HT, and 5-HIAA |
| Lee et al., 2015 [62], Korea | Silibinin | Parkinson's | Mice (C57B/6/M), n = 10 or 12 | 1 or 10 mg/kg, i.p., 5 days | MPTP | (i) Motor coordination and balance (rotarod test) | (i) DAB immunostaining: TH (ii) Double label immunostaining: GFAP and Iba-1 |
| Hu et al., 2016 [63], China | Baicalein | Parkinson's | Mice (C57BL/6/M), NR | 100 mg/kg, i.p., 7 weeks to 12 weeks | Rotenone | (i) Motor coordination and balance (rotarod test) (ii) Motor dysfunctions (grid test) |
(i) HPLC: DA, DOPAC, and HVA (ii) Immunofluorescence: α-syn, TH, and ChAT (iii) Real-time PCR: α-syn (iv) TEM (v) Western blot: α-synuclein and GAPDH |
| Zhang et al., 2017 [64], China | Baicalein | Parkinson's | Rats (SD/M), n = 15, or 10 | 100, 200, and 400 mg/kg, p.o., 28 days | Rotenone | (i) Locomotor activity (open field test) (ii) Motor coordination and balance (rotarod test) (iii) The inclined plane assessment |
(i) Immunohistochemistry: TH (ii) TEM (iii) TUNEL staining (iv) Western blot: caspase-3, PGC-1α, NRF-1, and TFAM |
| Goes et al., 2017 [65], Brazil | Chrysin | Parkinson's | Mice (C57B/6J/M), n = 6 | 10 mg/kg, p.o., 28 days | 6-OHDA | (i) Motor coordination and balance (rotarod test) (ii) Rotational behavior—numbers of rotations (apomorphine-induced circling behavior) |
(i) ELISA: IFN-γ, TNF-α, IL-6, IL-10, NF-κB, S100B, BDNF, GDNF, and NGF (ii) HPLC: DA, DOPAC, and HVA (iii) TRAP and TAR (iv) Immunohistochemistry: TH+ neurons |
| Ay et al., 2017 [66], USA | Quercetin and quercetin-containingformulation (QB3C) | Parkinson's | Mice (MitoPark and C57BL/6/M/F), n = 8 or n = 9 | Quercetin (25 mg/kg, p.o., 6 weeks) QB3C comprising quercetin (175 mg/kg, p.o., 8 weeks) |
MitoPark transgenic mouse models | (i) Locomotor activity (open field test) (ii) Motor coordination and balance (rotarod test) |
(i) HPLC: DA, DOPAC, and HVA (ii) DAB immunostaining: TH |
Animals: SD: Sprague-Dawley; W: Wistar; S: Swiss; SAMP8: senescence-accelerated prone mouse 8; NR: not reported. Parameters assessed: DPPH: 2,2-diphenyl-1-picrylhydrazyl radical; MDA: malonaldehyde; TBARS: thiobarbituric acid reactive substances; AAPH: 2,2′-azobis(2-methylpropionamidine) dihydrochloride; FeSO4: ferrous sulphate; 6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine; FJB: Fluoro-Jade B; GSH: reduced glutathione; GSSG: oxidized glutathione; AP-1: activator protein-1; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element-binding protein; p-CREB: phosphorylated; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: reduced glutathione; LDH: lactate dehydrogenase; CK: creatine kinase; AChE: acetylcholinesterase; MDA: malondialdehyde; p-tau: phosphorylated tau; TGF-β1: transforming growth factor beta 1; SYN: synaptophysin; p-AMPAR1: phospho-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; p-CRE: phosphorylated cAMP response element binding protein; p-CAMKII: phosphorylated calcium/calmodulin-dependent protein kinase II; p-PI3K: phosphorylated phosphatidylinositol-4,5-bisphosphate 3-kinase; p-Akt: phosphorylated protein kinase B; GFAP: antiglial fibrillary acidic protein; Iba-1: anti-ionized calcium-binding adapter molecule 1; 8-OxoG: 8-oxoguanine; p-JNK: C-jun N-terminal kinase; ICP-AES: inductively coupled plasma-atomic emission spectrometer; TEM: transmission electron microscopy; Aβ: brain expression levels of amyloid beta; BACE-1: beta-site APP cleaving enzyme 1; GSK3β: glycogen synthase kinase-3β; CDK5: cyclin-dependent kinase 5; GFAP: glial fibrillary acidic protein; NF-κB: nuclear factor kappa B; iNOS: inducible nitric oxide synthase; COX-2; NOS3; IL-1β; TNF-α; p-JNK: phospho-JNK; Bcl2; Bax; Cyt c: cytochrome c; FJB. RAGE receptor for advanced glycation end products; MnSOD: mitochondrial superoxide dismutase; NeuN: neuronal nuclei; LC3B: microtubule-associated protein light chain 3 isoform B; MS: mass spectrometry; DA: dopamine; DOPAC: dihydroxyphenylacetic acid; HVA: homovanillic acid; HO-1: hemeoxygenase; Nrf2: nuclear factor E2-related factor 2; GCLC: glutathione cysteine ligase regulatory subunit; GCLM: glutathione cysteine ligase modulatory subunit; JNK: c-Jun N-terminal kinase; MPP+: 1-methyl-4-phenylpyridinium; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; HPLC: high-performance liquid chromatography; ECD: equipped with electro chemical detector; TRAP: total reactive antioxidant potential; TAR: total antioxidant reactivity; S100B: calcium-binding protein B; GDNF: glial cell line-derived neurotrophic factor; NGF: nerve growth factor; DAB: diaminobenzidine; SA-β-Gal: senescence-associated β-galactosidase.