Table 1.
Effect of Juglans regia L. on learning and cognitive disorders
| Compound | Study design | Doses/Duration | Results | Ref. |
|---|---|---|---|---|
| In vitro | ||||
| Walnut extract | in vitro, PC12 cells | 2 or 4 μg | ↓ β-amyloid-mediated cell death, lactate dehydrogenase release, apoptosis, DNA damage, ROS generation | (53) |
| Lipophilic walnut extract | in vitro, SH-SY5Y cells | 10 μg/ml | ↑ ATP level, citrate synthase activity, neurite growth ↓ peroxidase activity, amyloid-β 1–40 |
(54) |
| In vitro and in vivo | ||||
| Defatted walnut meal |
in vitro, PC12 cells in vivo, mice |
0.10, 0.25, 0.50 mg/ml, 24 hr 167, 333, and 1000 mg/kg, 40 days, PO |
↑ antioxidant activity in PC12 cells ↓ apoptosis in PC12 cells ↑ learning and memory performance |
(93) |
| Hydrolysates from walnut |
in vitro, PC12 cells in vivo, mice |
0, 0.05, 0.1, 0.2, 0.5, 1, 2, 5 mg/ml, 24 hr 333.3 mg/kg, 4 weeks, PO |
↓ nonviable apoptotic cells in PC12 cells ↑ improved memory and consolidated memory ability |
(55) |
| Walnut protein hydrolysates |
in vitro, PC12 cells in vivo, rats |
0.10 mM, 24 hr 666 mg/kg body, 20 days, PO |
↑ SOD and GPx in PC12 cells ↓ apoptosis, ROS production, Ca2+ influx, and mitochondrial membrane potential collapse in PC12 cells ↑ behavioral performance, CAT, GPx, and SOD levels of the hippocampus ↓ MDA level |
(56) |
| Peptide from walnut |
in vitro, PC12 cells in vivo, zebrafish |
0, 1, 10, 30, 100, and 200 μg/ml, 24 hr 30, 100, 300 mg/kg, 7 days, PO |
↓ H2O2-induced cell death in PC12 cells ↑ mRNA expression level of BDNF significantly, more crossing times ↓ activity of caspases 3,7, and 8, mRNA expression levels of Bax and glial cell line-derived neurotrophic factor, escape latency, memory impairments |
(20) |
| Pro-Pro-Lys-Asn-Trp (PW5) |
in vitro, HEK-293-E22G in vivo, APP/PS1 transgenic mice |
0.05 and 0.5 mM, 48 hr 80, 400 mg/kg, 12 weeks, PO |
↑ serum norepinephrine and isovalerate levels, cognitive improvement ↓ β-amyloid plaque accumulation, serum levels of ACh and valerate |
(50) |
| Walnut peptides |
in vitro, BV-2 cells in vivo, mice |
0.10 mM 666 mg/kg, 21 days, PO |
↑ mitochondria homeostasis ↓ pro-inflammatory mediators and cytokines, ROS amount in BV-2 cells ↑ SOD, GPx, and CAT levels in the brain ↓ inflammation (PGE2, IL-6, IL-1β, and TNF-α) and oxidative stress in the brain |
(57) |
| 1-Hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-9,10-anthraquinone |
in vitro, zebrafish larvae in vivo, adult zebrafish |
15, 30 μM, for 72 hr 15, 30 μM |
- inhibited AChE ↑ learning and memory abilities ↓ acrylamide-induced neurotoxicity |
(47) |
| Walnut-derived peptide (YVLLPSPK) |
in vitro, HT-22 cells in vivo, mice |
100 μM), for 24 hr. 60 mg/kg, 4 weeks, PO |
↑ expression of mitophagy-related proteins and activated the NRF2/KEAP1/HO-1 pathway ↑ PINK1-mediated mitophagy ↓ cognitive deficiency, oxidative stress |
(58) |
| Gimcheon 1ho cultivar |
in vitro, PC12 and HT22 cells in vivo, mice |
20 and 50 μg/ml, 24 hr 20 and 50 mg/kg, four weeks, PO |
↑ cell viability ↓ ROS production ↓ behavioral and memory dysfunction, lipid peroxidation, cholinergic system impairment, FRAP, AGEs |
(94) |
| In vivo | ||||
| Walnut | in vivo, rats | 6% or 9% of the diet, 15 weeks, PO | ↑ autophagy, ATG7, and Beclin 1, ↓ polyubiquitinated protein aggregation, phosphorylation of mTOR, inflammation, and oxidative stress in the striatum and hippocampus |
(52) |
| Walnut kernel | in vivo, pregnant rats | 6% of diet during gestation and lactation, PO |
↑ learning and memory of rat offsprings |
(95) |
| Polyphenol extracts from walnut | in vivo, mice | 200 μg/g body weight, eight weeks, PO | ↑ number of crossings, brain SOD activity, learning and memory functions ↓ escape latency, swimming distance, brain MDA level |
(96) |
| Walnut | in vivo, mice | 6% or 9% of the diet, ten months, PO | ↑ memory function, learning ability, motor development ↓ anxiety |
(97) |
| Walnut | in vivo, rats | 2%, 6%, and 9% of the diet, four weeks, PO | ↓ memory impairments, AChE activity | (98) |
| Walnut protein hydrolysate | in vivo, mice | 0.2, 0.33, 0.66 g/kg, five days, PO | ↑ target times and crossing times in the spatial probe test, escape latency ↓ error times in the step-down avoidance test |
(99) |
| Walnut suspension |
in vivo, rats | 200, 400, or 800 mg/kg, 4 weeks, PO | ↑ ACh concentration in frontal cortex and hippocampus, SOD, CAT, and GPx amounts ↓ AChE activity, MDA level |
(59) |
| Walnut | in vivo, mice | 6% or 9% of diet, 5, 10, or 15 months, PO | ↑ the function of antioxidant enzymes ↓ oxidative stress, ROS, protein oxidation, and lipid peroxidation |
(60) |
| Walnut kernel powder | in vivo, mice | 500 and 1000 mg/kg, 14 days, PO | ↑ ACh level in the brain ↓ memory deficits, cholinesterase activity of the brain, total cholesterol amounts |
(61) |
| Walnut kernel | in vivo, rats | 6% and 9%, eight weeks, PO | ↑ hippocampal neurogenesis, hippocampal p-CREB, and BDNF expression ↓spatial memory loss, locomotor activity deficiency, recognition behavior reduction |
(62) |
| Walnut kernel and septum |
in vivo, rats | 9% of the daily diet given, 56 days, PO | ↑ antioxidant activity ↓ ROS and nitric oxide levels, AChE activity, onset of aging processes |
(63) |
| Walnut extract (60% ethanol) |
in vivo, mice | 10 and 20 mg/kg, three weeks, PO | - regulated BBB function ↑ mitochondrial function, SOD, ACh, and ATP levels ↓ behavioral dysfunction and memory deficit, MDA level, AChE activity, TNF-α, p-JNK, and IL-1β amounts |
(64) |
| Walnut oil | in vivo, mice | 10 ml/kg, eight weeks, PO | ↑ choline acetyltransferase activity, SOD activity, GSH amount ↓ memory impairment, AChE activity, MDA level in the brain, histological alterations of neurons in CA1 and CA3 regions of the hippocampus |
(65) |
| Walnut | in vivo, mice | 6% of the daily diet, 24 weeks, PO | ↑spatial memory, hydroxy-polyunsaturated fatty acids in the brain ↓arachidonic acid-based oxylipin levels |
(51) |
| Walnut protein hydrolysates | in vivo, mice and zebrafish | mice: 333, 666 mg/kg, 21 days, PO zebrafish: 20 mg/l, 7 days | ↑ expressions of antioxidant defense-related protein, BDNF, CREB, AChE and Keap1 inhibitors | (100) |
| Walnut derived peptide (WNP-10) | in vivo, mice | -88 differentially expressed proteins in the WNP–10-treated group - regulated phosphatidylinositol-3-phosphate 5-kinase, cathepsin L, N-acetylgalactosamine 6-sulfate sulfatase and AP-3 complex subunit mu-1 expression - maintained lysosome homeostasis ↑ learning and memory capability, phosphorylation of phosphatidylinositol-3-phosphate 5-kinase |
(66) | |
| Clinical trials | ||||
| Walnut | clinical trial, 708 free-living elders | 30–60 g/d, two years, PO | - delayed cognitive decline - no effect on cognition |
(67) |
| Whole walnut | clinical trial, 3632 US adults aged 65 years and older | 0·01–>0·08 1 oz. servings per day, 4-year, PO | - neuroprotective effects - positively linked with health behaviors and socioeconomic status ↑ cognitive scores |
(68) |
| Walnut oligopeptide | clinical trial, 36 teenagers and elderly people | 170 and 340 mg, 90 days, PO | ↑ adult intelligence scale, sleep quality index, average scores for test subjects of English, Mathematics, and Chinese examinations | (69) |
ACh: acetylcholine; AChE: acetylcholinesterase; AGEs: advanced glycation end products; ATP: adenosine triphosphate; ATG7: autophagy-related 7; Bax: Bcl-2 Associated X; BBB: blood-brain barrier; BDNF: brain-derived neurotrophic factor; CAT: catalase; DNA: deoxyribonucleic acid; FRAP: ferric reducing antioxidant power; GPx: Glutathione peroxidase; GSH: glutathione; IL-1β: interleukin 1 beta; MDA: malondialdehyde; mRNA: messenger ribonucleic acid; mTOR: mammalian target of rapamycin; NRF2/KEAP1/HO-1: nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1/ Heme oxygenase-1; p-CREB: phosphorylated cAMP response element-binding protein; PGE2: Prostaglandin E2; p-JNK: phosphorylated c-Jun N-terminal kinase; PINK1: PTEN-induced putative protein kinase 1; p.o.: oral; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumor necrosis factor-alpha