Table 1.

Preclinical studies that assessed the efficacy of natural and synthetic molecules with antioxidant properties in cellular and murine models of Down syndrome (DS).

Antioxidant Drug	Model of DS	Dosage and Treatment Duration	Results	References
Vitamin E (α-tocopherol)	Adult Ts65Dn mice (4 months of age)	50 ± 5 mg/kg/day supplemented in the diet for 5 months	Improvement of spatial memory, reduction of cholinergic neurodegeneration, normalization of OS markers	[77]
	Pregnant Ts65Dn females and their pups	Pregnant Ts65Dn females received (0.1% (w/w) α-tocopherol acetate per kilogram of diet) from the day of conception throughout the pregnancy and the pups received the same diet from the day of birth for 12 weeks	Reduction of levels of lipid peroxidation products, attenuation of cognitive impairment, improvement of the hippocampal hypocellularity	[79]
SGS-111	DS cortical neurons cultures	Various doses from 10 nM to 100 µM (30 min before the addition of H2O2 to the cultures and until 24 h later)	Inhibition of the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H2O2. Reduction of the appearance of degenerative changes and increment of neuronal survival	[99]
	Adult Ts65Dn mice (6 months of age). Pregnant Ts65Dn females and their pups over their entire life (5 months)	In both studies: 0.5 mg/kg (daily subcutaneously injected). Duration of adult treatment: 6 weeks. Duration of pre- and postnatal treatment: 5 months	No evidence of changes in behavior or cognition	[110]
Melatonin	Adult Ts65Dn (6 months of age)	0.5 mg/day in their drinking water for 6 months	Improvement in spatial learning, reduction of cholinergic neurodegeneration, improvement of hippocampal neurogenesis, reduction of synaptic inhibition, restoration of hippocampal LTP, reduction of protein and lipid oxidative damage and of the density of senescent cells in the hippocampus	[81,82,102]
	Pregnant Ts65Dn females and their pups	0.5 mg/day in their drinking water during pregnancy to TS females until the weaning of the offspring, and to the pups until the age of 5 months	No effect on cognitive or neurogenesis abnormalities. Modulation of antioxidant enzymes: SOD in the cortex, and catalase in the hippocampus. No effect on lipid and protein oxidative damage	[80]
7, 8-dihydroxyflavone	Ts65Dn pups, young and adult stages	In all studies: 5 mg/kg (daily subcutaneously injected). Postnatal treatment: for 12 days. Adolescent treatment: from P3 to adolescence (P45–50) Adult treatment: 6 weeks	Postnatal treatment: restoration of hippocampal neurogenesis and dendritic spine development, but 1 month after cessation of the treatment there was no evidence of pro-cognitive effects. Adolescent treatment: improvement in cognition. Adult treatment: no effect on cognition	[111,112]
Apigenin	Ts1Cje mothers and their pups	200–250 mg/kg/day in chow, during pregnancy to the mothers and to their pups up until 8–10 weeks of postnatal life	Improvement of exploratory behavior	[113]
Epigallocatechin-3-gallate (EGCG)and Resveratrol	Neuronal progenitor cells isolated from the hippocampus of the Ts65Dn mouse	EGCG and Resveratrol, 20 μM and 10 μM, respectively, for 24 h	Restoration of mitochondrial homeostasis and promotion of proliferation in neuronal progenitors	[83]
Epigallocatechin-3-gallate	Ts65Dn pups	25 mg/kg in a daily subcutaneous injection from postnatal day 3 to postnatal day 15	At P15 the treatment rescues hippocampal neurogenesis. This effect was not evident 1 month later after cessation of the treatment	[114]
	Ts65Dn pups	0.4 mg/mL in their drinking water (≈50 mg/kg/day) from postnatal day 24 to postnatal day 68 (≈6 weeks)	No improvement in cognitive deficits and produced detrimental skeletal effects	[115]
	Young adult Ts65Dn (3 months of age)	90 mg/mL for a dose of 2–3 mg per day in drinking water for 1 month	Improvement of hippocampal-dependent learning deficits	[116]
Curcumin	Pregnant Ts65Dn mice and their pups and young mice	In both studies: 300 mg/kg in a daily subcutaneous injection. Prenatal treatment: from embryonic day 10 to postnatal day 2. Postnatal treatment: from postnatal day 2 to postnatal day 15	Prenatal effects: increase in brain weight, cell proliferation, and pro-cognitive long-term effects. Postnatal effects: no effect on cognition	[117]
Glucagon-like peptide 1	Adult Ts65Dn mice (9 months of age)	500 ng/g daily via intraperitoneal injection for 2–3 weeks	Reduction of mitochondrial ROS generation, of dendritic spine morphology alterations, and improvement of LTP and cognitive alterations	[118]
Rapamycin	Adult Ts65Dn mice (6 months of age)	Three times per week with a dose of 0.1 μg/μL (1 μg/mouse) by intranasal route for 12 weeks	Restoration of mTOR pathway and reduction of lipoxidized proteins, rescue of autophagy and insulin signaling. Improvement in cognition	[96,98]
Pioglitazone	Trisomic fetal fibroblasts	5 mM for 3 days	Improvement of mitochondrial bioenergetics: increase of basal ATP content and oxygen consumption rate and decrease of ROS production	[119]
Metformin	Trisomic fetal fibroblasts	0.05 or 0.5 mM for 3 days	Reduction of mitochondrial abnormalities: increases in ATP production, oxygen consumption rate, and mitochondrial activity. Reversion of mitochondrial fragmentation and promotion of mitochondrial network	[24]