Table 3.

Therapies targeting autophagy pathways in CNS WMDs.

	Compound	Mode of action	Effects in WMDs	Reference
Autophagy inducers
Targets of mTOR	Rapamycin	Inhibits mTOR	Ameliorates EAE by blocking immune cell activation. May be effective in PND. Improves viability of M03.13/EIF2B3 cells	[51, 102, 103]
	Ridaforolimus	Inhibitor of mTOR complexes	Improves viability of M03.13/EIF2B3 cells	[70]
	Temsirolimus	Rapamycin analogue	Prevents protein accumulation, energetic failure and proteasome malfunctioning in Abcd1 − mice	[60]
	Pp242	Inhibits the active site of mTOR	Blocks Akt phosphorylation	[104]
	Torin 1	mTOR inhibitor	Unknown	[105]
mTOR ATP competition	Resveratrol	Inhibits mTOR–ULK1 pathway	Unknown	[106]
AMPK activation	Pinosylvin	Induces conversion of LC3‐I to LC3‐II, and activates AMPK	Unknown	[107]
	Chebulagic acid	Increases phosphorylated AMPK	Protects against cytotoxicity in SH‐SY5Y cells	[108]
	Metformin	Activates AMPK by increasing cytosolic AMP	Reduces lesions in cuprizone model Rejuvenates OPC ageing Reduced lesion load in MS	[109, 110, 111, 112]
Akt–mTOR modulation	Gefitinib	Inhibits PI3K/Akt/mTOR pathways	Unknown	[113]
	RY10‐4	Inhibits phosphorylation of Akt and mTOR	Unknown	[114]
	Berberine	Inhibits upstream mTOR signalling and MAPK phosphorylation	Unknown	[115]
	Concanavalin A	Inhibits PI3K/Akt/mTOR pathways	Unknown	[116]
	Curcumin	Inhibits PI3K/Akt/mTOR pathways	Ameliorates EAE progression and delays onset	[51]
	Tunicamycin	Induces ER stress	Unknown	[117]
	Erlotinib	Inhibits PI3K/Akt/mTOR pathways	Unknown	[113]
	Piperlongumine	Inhibits PI3K/Akt/mTOR pathways	Unknown	[118]
	Baicalein	Decreases expression of Akt/ULK1 and 4EBP1	Unknown	[119]
	Plumbagin	Inhibits PI3K/AKT/mTOR pathways	Unknown	[120]
	Emodin	Increases LC3‐II	Unknown	[121]
	Ivermectin	Promotes degradation of PAK1	Unknown	[122]
	Corynoxine	Inhibits PI3K/AKT/mTOR pathways	Unknown	[64]
NOS inhibitor	L‐NAME	Inhibits NOS activity	Unknown	[123]
Reducing cAMP	Rilmenidine	Binds to imidazoline‐1 receptor to reduce cAMP	Unknown	[124, 125]
	Clonidine	Binds to imidazoline‐1 receptor to reduce cAMP	Unknown	[124]
	H89	Inhibits cAMP‐dependent protein kinase	Unknown	[126]
	HU‐308	Activates CB2R	Ameliorates EAE progression	[127]
Targeting ULK1/2 or class III PI3K complexes	BH3 mimetics	Inhibits Beclin‐1 interaction with Bcl‐2	Unknown	[128]
	Glycyrrhizic acid	Induces Beclin‐1 production	Unknown	[129]
MicroRNAs	miRNA‐18	Inhibits mTOR signalling pathway	Unknown	[130]
	miRNA‐21	Upregulates Bcl‐2 expression	Unknown	[131]
Enhanced ROS production	Cucurbitacin B	Increases expression of Beclin‐1, ULK1, reduces expression of mTOR	Unknown	[132]
Lowering inositol synthesis	Lithium	Inhibits inositol monophosphate	Reduces aggregates of GFAP in a mouse model of Alexander disease	[133, 134]
	Carbamazepine	Inhibits inositol monophosphate	Unknown	[135, 136]
	Sodium valproate	Inhibits inositol monophosphate	Unknown	[135, 136]
Autophagy inhibitors
Akt–mTOR modulation	Pollen typhae	Increases LC‐3 and Beclin‐1	Unknown	[137]
	Gastrodin	Decreases LC3‐II, p62 and Beclin‐1	Protects astrocytes in vitro from LPS‐induced cell death	[138]
	Bafilomycin A1	Blocks lysosome fusion with autophagosomes	Unknown	[139]
	Spautin‐1	Promotes degradation of Vps34 by inhibiting ubiquitin‐specific peptidases	Unknown	[140]
	Chloroquine	Blocks lysosome fusion with autophagosomes	Ameliorates EAE disease severity	[141]
ERK kinase inhibitor	U0126	Inhibits ERK	Unknown	[142]
PI3K inhibitor	3‐methyladenine	Blocks class III PI3K	Increased severity of EAE and inflammation	[102]
	Wortmannin	Blocks autophagosome formation	Unknown	[138]
	Matrine	Blocks autophagosome formation	Reduces stress in oligodendrocytes in EAE	[143]
Other	Angiotensin (1–7)	Reduces oxidative stress	Unknown	[144]
MicroRNAs	miRNA‐30a	Suppresses expression of TP53INP1	Unknown	[145]
	miRNA‐205	Suppresses expression of TP53INP1	Unknown	[145]
	miRNA‐101	Suppresses RAB5A	Unknown	[146]
	miRNA‐223	Targets ATG16L1	Unknown	[147]

GFAP, glial fibrillary acidic protein; LPS, lipopolysaccharide; OPC, oligodendrocyte precursor cell; PND, paraneoplastic neurological disorder.