Melatonin supplementation inhibits amyloidogenesis and attenuates neurodegenerative disorders
| Melatonin dosage/duration | Study design | Results | Ref. |
|---|---|---|---|
| 50 mg/kg body weight (b.w.) via intraperitoneal (IP) injection for 40 days | Young adult male Sprague-Dawley (SD) rat Alzheimer’s disease (AD) model induced by intracerebroventricular (icv) infusion with amyloid-beta (Aβ)1–42 (100 μg) + pinealectomy | Melatonin treatment in icvAβ1–42 + pinealectomy rats, icvAβ1–42-, or pinealectomy-only rats significantly rescued impaired spatial memory and reduced accumulation of Aβ1–42 and γ-secretase | [225] |
| 20 mg/kg b.w. via oral route for 40 days | Male Wistar rat AD model, induced by icv streptozotocin (STZ) injection (3 nmg/kg b.w.) | Melatonin treatment improved cognitive performance of AD rats, reducing amyloid stimulation of microglia activation in hippocampal CA1 and CA3 regions | [236] |
| 10 mg/kg b.w. via IP njection for 30 days | Male Rattus norvegicus Wistar rat AD model, induced by icv-STZ injection (3 nmg/kg b.w.) | Melatonin reversed cognitive impairment in the spatial version Y-maze test and suppressed the accumulation of Aβ induced by icv-STZ injection | [237] |
| 0.5 mg per mouse per day in drinking water for 3 months | APP/PS1 (mutant APP and PS1 transgenic) AD and C57/BL6J mice as controls | Melatonin-treated transgenic mice, compared to controls, exhibited improved cognitive function and reduced deposition of Aβ plaques via suppression of NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation and increased transcription factor EB (TFEB) nuclear translocation | [238] |
| 100–5000 μM melatonin | In vitro study—aggregation/disaggregation of repeat domain tau (K18wt) performed in assays without adenosine triphosphate (ATP) | A dose-dependent disaggregation of preformed tau aggregates was observed: 14% with 100 μM, 54% with 5000 μM | [239] |
| 200–5000 μM melatonin | In vitro study—aggregation/disaggregation full-length tau (hTau40wt) by melatonin in Neuro2A cells | Tau treated with 200 μM melatonin showed no change in morphology compared to controls; 5000 μM melatonin treatment did not prevent aggregation but disaggregated tau fibrils into broken filaments | [240] |
| 0.3 mg per mouse in drinking water from day 7 after tauopathy induction to day 28 at termination | 4-month-old C57BL/6J mice injected with human tau mutation P301L (AAV-hTau) | Increased ROS and tau hyperphosphorylation starting at day 7 precedes cognitive decline; melatonin treated animals showed reduced memory impairment, tau hyperphosphorylation, ROS, and neuroinflammation | [241] |
| 10 μM/L melatonin | Ex vivo brain slices from human and 3-month-old SD rats exposed to okadaic acid (OA) to induce tau hyperphosphorylation | Melatonin reduced tau hyperphosphorylation and ROS to control levels in OA-treated human and rat brain slices | [241] |
| ~6 mg melatonin per mouse daily in drinking water starting at age 4 months until euthanasia | Transgenic Tg2576 AD mice, terminated at 4 months 1 week or 15.5 months | The brains of animals treated with melatonin terminated at 15.5 months exhibited impressive declines in oligomeric Aβ40/Aβ42 together with significantly increased lymphatic clearance of soluble monomeric Aβ40 and Aβ42 compared to untreated mice at the same age. Survival rates of melatonin-treated transgenic mice at 15.5 months were similar to wildtype controls | [242] |
| 10 mg/kg (IP) daily for 3 weeks | Male wild-type C57BL/6N mice (8 weeks old) injected with Aβ1–42 peptide | Melatonin treatment reversed Aβ1–42-induced synaptic disorder, memory deficit, and prevented Aβ1–42-induced apoptosis, neurodegeneration, and tau phosphorylation | [243] |
| 25 µM and 250 µM melatonin | In vitro α-synuclein (α-syn) peptide aggregation in primary neuronal cultures | Melatonin blocked α-syn fibril formation and destabilized preformed fibrils in a dose- and time-dependent manner; increased viability of primary mixed neurons treated with α-syn to ~97% in a time-dependent manner | [244] |
| Melatonin (50 mg/kg b.w.) IP injection for 5 days | Arctic mutation (E22G) male Swiss albino AD mice induced by Aβ1–42 synthetic peptides (scrambled and protofibrils) via icv injection | Melatonin treatment in Aβ protofibril-injected mice restored brain glucose levels to protect ATP production; inhibited ROS production and maintained homeostasis of antioxidant enzymes, intracellular calcium and acetylcholine levels in neuronal cells compared to controls and mice injected with scrambled AB1-42 peptides | [245] |
| 10 mg/kg (IP) × 5/day for 2 days, then × 2/day for 5 days | Arsenite-induced oxidative injury in substantial nigra of adult male SD rats | Reduced arsenite-induced α-syn aggregation, lipid peroxidation, and glutathione depletion | [246] |
| ~65 µg melatonin per mouse (2.6 mg/kg b.w.) in drinking water for 10 weeks, starting at age 14 months | Transgenic Tg2576 AD mice | Melatonin treatment failed to reduce brain Aβ levels or even oxidative damage | [247] |
| 40-ppm (w/w) in pelleted minimal basal diet (~5 mg/kg b.w.) for 11 weeks | Male B6C3F1 mice aged 6, 12, and 27 months | Significant reduction of Aβ in brain cortex tissues: 57% in Aβ40 and 73% in Aβ42; increased melatonin levels in cerebral cortex in all 3 treated age groups (12 > 6 > 27 months) compared to untreated | [248] |
| 6 mg melatonin per mouse daily in drinking water starting at age 4 months until euthanasia at 15.5 months | Transgenic Tg2576 AD mice | Increased survival in treated mice (3 deaths, 41 survivals) compared to untreated controls (13 deaths, 31 survivals) | [249] |
| 1.5 mg melatonin per mouse daily in drinking water starting at age 4 months | Transgenic Tg2576 AD mice | Striking reductions in Aβ levels in brain tissues of treated mice at 8, 9.5, 11, and 15.5 months | [249] |
| 0.3 mM melatonin dissolved in 2 mM ammonium acetate | In vitro study—Aβ peptide (1–40) β-sheet/fibril formation | Inhibited β-sheet formation by targeting hydrophobic Aβ-peptide segment (29–40) intermolecular activities | [250] |
| 1 nM–200 µM melatonin | In vitro study—Aβ synthetic peptides (1–40) and (1–42) β-sheet/fibril formation | Progressive reduction of Aβ1–40 β-sheet structures to 24% after 24 h incubation; immediate reduction of Aβ1–42 β-sheet structures from 89% to 65%, decreasing to 59% after 4 h; complete disaggregation into amorphous material after 6 h (100 μM melatonin, 250 μM Aβ1–40 peptides) | [251] |
ppm: parts per million; w/w: weight per weight
Note. Adapted from “Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia” by Loh D, Reiter RJ. Int J Mol Sci. 2023;24:5835 (https://doi.org/10.3390/ijms24065835). CC BY.
