Table 4.

Table showing the main findings regarding the effects of melatonin on neurogenesis in aging and neurodegenerative diseases and the respective molecular mechanisms in the in vivo studies.

Animals	Treatment Timeline and Dosage	Brain Regions	Main Findings	Behavioral Outcomes	Molecular Mechanisms	References
Male C57BL/6 mice subjected to d-galactose (d-gal) for 7 weeks (animal model of aging)	6 mg/mL melatonin in drinking water for 3 weeks	Dentate gyrus	Restored d-gal-induced reduction of Ki67+ proliferative cells and DCX+ neuronal precursor cells	Improved spatial memory (Morris water maze)	Increased Ser133-phosphorylated cyclic AMP response element binding protein; decreased d-gal-induced lipid peroxidation	Yoo et al., 2012 [59]
10-month-old senescence-accelerated mice (SAMP8) (animal model of aging)	≈10 mg/kg BW melatonin, via drinking water (from 1 month old to 10 months old)	Brain	Effects on neurogenesis were not examined in the study	Not examined in the study	Decreased acetylated p53 and NF-κB; increased α-secretase; decreased amyloid β (Aβ); increased Bcl-2XL levels	Gutierrez-Cuesta et al., 2008 [61]
8-week-old male C57BL/6 mice treated with methamphetamine (METH) (animal model of Parkinson’s disease)	5 mg/kg BW melatonin, subcutaneously injected for 7 days	Hippocampus	Increased expressions of Nestin, DCX, and Beta-III tubulin	Not examined in the study	Attenuated the METH-induced change in MAPK signaling activity, NMDA receptor subunits (NR2A and NR2B) and CaMKII	Singhakumar et al., 2015 [62]
B6C3-Tg (APPswe, PSEN1dE9)85Dbo/Mmjax transgenic male mice (animal model of Alzheimer’s disease) or mice subjected to 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid over 5 weeks (animal model of Parkinson’s disease)	Transplanting 25 μM melatonin-pretreated SVZ NSCs in both disease models	Hippocampus or striatum	Effects on neurogenesis were not examined in the study	Reduced Aβ plaques in the AD transgenic mouse model Improved neuronal restoration in the PD mouse model	Not examined in the study	Mendivil-Perez et al., 2017 [63]
Adult male SD rats subjected to 6-hydroxydopamine (6 OHDA) in the striatum by stereotaxic injection (animal model of Parkinson’s disease)	4.0 μg/mL melatonin in drinking water for 39 days or 4.0 μg/mL melatonin in drinking water for 39 days, plus C17.2 NSC transplantation	Striatum and substantia nigra	Combination treatments preserved tyrosine hydroxylase (TH) immunoreactivity	Reduced apomorphine-induced rotations	Not examined in the study	Sharma et al., 2007 [64]
8-week-old male C57BL/6 mice given 0.2% cuprizone in the chow diets (animal model of demyelinating disease)	6 mg/L melatonin in drinking water for 6 weeks	Dentate gyrus	Ameliorated cuprizone-induced reduction of DCX+ neuronal precursor cells and Ki-67 proliferating cells	Not examined in the study	Increased glucose utilization (GLUT3); increased pCREB; increased BDNF	Kim et al., 2019 [65]
APP/PS1 mice (animal model of Alzheimer’s disease)	≈0.1 mg/kg BW melatonin, via drinking water (starting from 4 to 8 months of age)	Cortex and the hippocampus	Effects on neurogenesis were not examined in the study	Reduced spatial learning and memory deficits	Increased levels of mitochondrial biogenesis factors; enhanced mitochondrial DNA copy number; reduced Aβ	Song et al., 2018 [66]