Table 1.

Autophagy-modulating compounds in PD.

Target	Origin	No.	Agent	Main effect	PD model	Reported year in PD	Ref.
AMPK	Natural product	2	Resveratrol	Prevented loss of DA neurons; rescued TH and DA levels; improved behavioral abnormalities	MPTP treated mice	2008	43
		8	Caffeine	Reduced p129-α-syn; apoptosis; microglial activation; astrogliosis; increased LC3II/I ratio	A53T α-syn transgenic C57BL/6J mice	2001	76
	Chemical synthesis	1	Metformin	Reduced levels of p-Ser129 α-syn in vivo and in vitro, increased striatal dopaminergic levels	α-Syn overexpressing SH-SY5Y cells and C57BL/6J mice	2014	44
		3	A769662	Reduced levels of α-syn inclusions	α-Syn overexpressing SH-SY5Y cells	2019	75
		4	GSK621	Reduced levels of α-syn inclusions	α-Syn overexpressing SH-SY5Y cells	2019	75
		5	Rosuvastatin	Increased cell viability; increased α-syn clearance	Rotenone-exposed SH-SY5Y cells	2017	55
		6	FCPR16	Protected neuronal cells against MPP+-induced toxicity and oxidative stress	SH-SY5Y cells treated with MPP+	2018	66
		7	Temozolomide	Increased α-syn clearance and protected α-syn-induced cytotoxicity	α-Syn overexpressing LUHMES cells	∖	74
mTORC1	Natural product	9−11	Rapamycin and Rp analogues (CCI-779 and AP23573)	Increased the clearance of WT, A30P and A53T α-syn	α-Syn expressing PC12 cells	2010	77
				Prevented neuronal death in mice; reduced α-syn accumulation, improved motor function	MPTP treated mice; α-syn transgenic mice	∖	50,51
		12	Corynoxine	Promoted the clearance of wild-type and mutant α-syn via autophagy	α-Syn overexpressing PC12 cells	2014	78
		13	Loganin	Decreased MPTP-induced neurotoxicity	MPTP treated PC12 cells	2017	79
	Chemical synthesis	14	PI-103	Increased α-syn clearance and protected α-syn-induced cytotoxicity	α-Syn overexpressing Lund human mesencephalic (LUHMES) cells	∖	74
ULK1	Chemical synthesis	15	BL-918	Protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons	MPP+-treated SH-SY5Y cells	∖	45
IMPase	Chemical synthesis	16	Sodium valproate	Enhanced autophagy, reduced mitochondrial membrane potential, reduced production of reactive oxygen species and enhanced cell viability	Rotenone-induced SH-SY5Y cells	∖	46
		17	Carbamazepine	Enhanced autophagy, reduced mitochondrial membrane potential, reduced production of reactive oxygen species and enhanced cell viability	Rotenone-induced SH-SY5Y cells	∖	46
		18	L-690,330	Increased α-syn clearance and protected α-syn-induced cytotoxicity	α-Syn overexpressing LUHMES cells	2019	74
LRRK2	Chemical synthesis	19	LRRK2-IN-1	Rescued Lrrk2 G2019S mutant motor injury	Drosophila	∖	48
		23	GNE-7915	Enhanced DA release and recovery	R1441G transgenic mice	∖	47
		25	PF-06447475	Reduced neuronal apoptosis and alleviated neurological deficit	Weight-drop Sprague–Dawley rats after traumatic brain injury	∖	130
			DNL151a			∖	49
			DNL201a			∖	49
Beclin-1	Natural product	29	Isorhynchophylline	Promoted clearance of wild-type, A53T and A30P α-syn	Differentiated human dopaminergic neurons	2014	53
		30	Corynoxine B	Reversed reduction in LC3-II and BECN1; restored the deficient autophagy induced by SNCA	α-Syn overexpressing PC12 cells	2019	54
		31	Glycyrrhizic acid	Increased cell viability; up-regulated LC3-II/I and beclin-1	6-OHDA and crticosterone treated SH-SY5Y cells	2018	56
	Chemical synthesis	28	KYP-2047	Enhanced autophagy and α-syn clearance; increased in striatal dopamine levels	A30P α-syn transgenic mice	∖	52
TFEB	Natural product	32−35	Curcumin and Cur analogues (CNB001, C1 and E4)	Inhibited the accumulation of α-syn and prevented the accumulation of LB	α-Syn overexpressing SH-SY5Y cells	∖	57, 58, 59, 60, 61, 62
		36	Trehalose	Reduced the loss of SNpc DA neurons and produced a neuroprotective effect	Multiple PD related models	2004	63
GCase	Chemical synthesis	37	Ambroxola	Increased GCase activity and reduced oxidative stress	PD fibroblasts with Gba1 mutations	2014	64,65,158
		38	Isofagomine	Increased GCase levels and activity; lowered ER stress and prevented the loss of motor function	PD fibroblasts with Gba1 mutations; Drosophila	∖	67
		39	NCGC607	Restored GCase activity and protein levels; reduced α-syn levels	iPSC-derived macrophages and dopaminergic neurons	∖	68
ERRα	Chemical synthesis	40	XCT790	Alleviated dopaminergic neuronal loss; cleared toxic protein aggregates; ameliorated behavioral impairments	MPTP treated mice	2018	69,70
c-ABL	Chemical synthesis	41	PD180970	Cleared toxic α-syn protein aggregates; alleviated behavioral impairments	α-Syn overexpressing SH-SY5Y cells and MPTP induced mice	2019	71
		42	Imatinib	Reduced expression of c-ABL and p-GSK3β; restored ALP and decreased cells death	MPP+-induced SN4741 cells	2014	72
		43	Nilotiniba	Reduced c-ABL activation, prevented dopamine (DA) neuron loss and behavioral deficits; induced α-syn degradation in vivo and in vitro	MPTP-induced mice; α-syn overexpressing primary cultures of mouse cortical neurons and mice	2014	72,73

^aDrugs which have already entered clinical trials. DNL151 (NCT03710707) and DNL201 (NCT04056689) in phase Ⅰ trial while nilotinib (NCT02954978; NCT03205488) and ambroxol (NCT02941822) are in phase Ⅱ trail. Data source: http//clinicaltrials.gov; November 2020.