Table 1.

List of all the compounds used in DS neuropathology in clinical and preclinical studies acting on the Unfolded and Integrated stress Response, autophagy and ROS.

Compound	Structure	Target	Study Type	Dosage	Length of the Treatment	Administration Route	Model	Ref.	Outcomes
Unfolded Protein Response and integrated stress Response inhibitors
GSK2606414		PERK	Preclinical study	0.1 μg/μL	5 days (1× day)	intranasal treatment	Ts2Cje	[61]	Restored protein synthesis; reduced OS
ISRIB		eiF2a	Preclinical study	2.5 mg/kg	7 days (once every 2 days)	i.p. injection	Ts65dn	[62]	Restored protein synthesis; improved long-term memory
PKRi		PKR	Preclinical study	0.1 mg/kg	6 days (1× day)	i.p. injection	Ts65dn	[216]	Rescued long-term memory and synaptic plasticity
Autophagy inducers
Rapamycin		mTOR	Preclinical study	10 mg/kg	5 days	i.p. injection	Ts1Cje	[223]	Restored spatial long-term memory
		mTOR	Preclinical study	1μg	90 days (1× day, 3× week)	intranasal treatment	Ts65dn	[63,187]	Restored autophagy; rescued cognitive performances, reduced AD hallmarks and OS
Thiamet G		O-GlcNAcase	Preclinical study	25 ug	5 days (2× day)	intranasal treatment	Ts2Cje	[56]	Restored proteostasis; rescued autophagy
Choline		phospholipids/ neurotransmitter	Preclinical study	5.0 g/kg choline chloride	≃ 21 days	maternal supplementation	Ts65dn	[224]	Restored autophagy and endosomal pathway; improved cognition
AZD8055		mTORC1/2	Preclinical study	0.1 μM	2, 4 and 8 h	cell treatment	Human fibroblast	[60]	Rescued autophagy; rescued mitophagy
Antioxidant molecules
α-tocopherol (vitamin E)		ROS	Preclinical study	50 mg/Kg	5 months	diet supplementation	Ts65dn	[195]	Reduced OS; improved spatial working memory
		ROS	Preclinical study	0.1% w/w for Kg of diet	Pregnancy and pups	maternal supplementation	Ts65dn	[196]	Improved cognition; reduced lipid peroxidation
		ROS	Randomized, double-blind, placebo-controlled trial	900 IU+ ascorbic acid (200 mg) + α-lipoic acid (600 mg)	2 years (daily)	oral	DS and AD individuals	[197]	No cognition improvement
		ROS	Randomized, placebo-controlled clinical trial	1000 IU	over 3 years (twice daily)	oral	DS over 50 years	[199]	No cognitive improvement
		ROS	randomized controlled trial	266 mg + α-lipoic acid (100 mg/day)	4-months (daily)	oral	DS children	[200]	Reduced OS at DNA level
		ROS	Clinical study	400 mg + Vitamin C (500 mg/day)	over 6 months (daily)	oral	DS children and teenagers	[201]	Reduced blood levels of lipid peroxidation
Coenzyme Q10		ROS	Clinical study	4 mg/kg	6 or 20 months (daily)	oral	DS children	[203]	Reduced OS at DNA level
		ROS	Clinical study	4 mg/kg	4-year (daily)	oral	DS children	[204]	No reduced OS at RNA or DNA level
Melatonin		ROS	Preclinical study	(0.5 mg/day)	5 months	water supplementation	Ts65dn	[205,206,207,208]	Improved spatial learning and memory; rescued neurogenesis
Apigenin		ROS	Preclinical study	333–400 mg/kg	≃ 45 days (pregnancy and lactation)	maternal supplementation	Ts1Cje	[209]	Improved postnatal behavior
EGCG		DYRK1A; ROS	Preclinical study	20 μM	72 h (changed every 24 h)	cells treatment	Human DS cell cultures	[210]	Reduced OS and mitochondrial energy deficit
			Preclinical study	2–3 mg/day	1 month	water supplementation	Ts65Dn/TgDyrk1A	[211]	Improved cognition
			Preclinical study	225 mg/kg/day	4 weeks	water supplementation	Ts65Dn	[212]	Restored excitatory/inhibitory (E/I) imbalance (GABA modulation)
			Preclinical study	25 mg/Kg/day	P3 to P15	subcutaneous injection	Ts65Dn	[64]	Restored neurogenesis at P15; no cognitive improvement at P45
			Preclinical study	30 mg/kg/ day	30 days	water supplementation	Ts65Dn	[213]	Rescued CA1 dendritic spine density, improved cognition
			Preclinical study	50 mg/kg	T1 (21 days) T2 (mating until 90 days) T3(P60-P90)	diet supplementation	Dp(16)1Yey	[214]	Rescued GAD67; restored VGAT1/VGLUT1 balance; improved novel object recognition memory
			phase I randomized controlled clinical trials	9 mg/kg/day	6 months	diet supplementation	Young adults with DS	[211]	Reduced plasma homocysteine; rescued cognitive performances
			double-blind, placebo-controlled, phase II trial	9 mg/kg/day	12 months	diet supplementation	Young adults with DS	[215]	Improvement in adaptive behavior