Targeting remyelination treatment for multiple sclerosis

Table 1 Known pathways affecting remyelination in multiple sclerosis

Pathway	Potential protein targets	Drugs	Ref.
Hyaluronan	TLR2	TLR2 Ab (OPN-305)	[28]
	Hyaluronidase	Vcpal	[28,30]
Notch-1	Notch-1	(pan) BMS-906024	[14,15,17,19]
	Jagged-1	-	[14]
	Endothelin-1	PD142,893, sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, bosentan, macitentan, tezosentan	[17]
	γ-secretase	MW167, LY450139	[93]
Retinoid X receptor	RXR-γ	Bexarotene, IRX4204	[31]
Wnt/ß-catenin	ß-catenin	PKF118-744, CGP049090, PKF118-310, XTM000990, BC21, PKF115-584, PNU-74654	[21,22]
	Tankyrases 1-2	XAV939, IWR1, JW74, JW55	[57]
	GSK3ß	SB216763	[20]
LINGO-1	LINGO-1	Anti-LINGO-1 Ab	[23-25]
CXCL12/CXCR4	CXCR7	CCX771	[37,38]
	CXCR4	AMD3100	[37,38]
GPR17	GPR17	Unnamed	Omeros

TLR2: Toll-like-receptor 2; GPR17: G protein-coupled receptor 17; CXCL4: C-X-C chemokine receptor type 4; CXCL12: Chemokine (C-X-C Motif) ligand 12.

Table 2 Drug classes identified in remyelination screens

Drug class	Compounds	Ref.
Adrenergic agonist	Methoxamine, nerepinephrine, tolaxoline, salmeterol	[55]
Dopamine antagonists	Opipramol, flupentixol, fluphenazine, trifluoperazine, perphenazine, quetiapine	[55,57]
Dopamine uptake inhibitor/dopamine agents	Vanoxerine, GBR12935, methyldopa	[55]
Histamine antagonists	Clemastine, doxylamine, clemizole	[55,57]
Adrenergic antagonist	Opipramol, trifluoperazine, Cgp-26505, tolazoline, quetiapine	[55,57]
Anticholinergics/cholinesterase reactivators	Homatropine, clemastine, benztropine, disopyramide, trospium, diacetyl-monoxime, tiotropium, oxybutynin, atropine, ipratropium, hyosamine, atropine, methy atropine, octatropine, glycpyrrolate, carbetapentane, piperildolate, bevonium, propiverine, dicyclomine, mepenzolate, trihexylphenidyl	[55,57]
Phosphodiesterase inhibitor	8-bromo cyclic GMP, IBMX, enprofylline, enoximone, rolipram	[55]
PPAR agonist	GW-1929	[55]
Ion channel blockers	Gabapentin, 8-aminobenzoic acid, disopyramide, oubain	[55]
Serotonin modulators	Brl-15572, paroxetine, clemizole, quetiapine	[55,57]
Glutamate receptor antagonist	UPF-523, l-aminodan-1,5-dicarboxylic acid	[55]
Beta-catenin inhibitor	XAV939	[55]
Retinoic acid receptor agonist	Retinoids, AM580	[55,94]
Thyroid hormone receptor agonist	T3	[55,57]
COX-2 inhibitors	Niflumic acid, flunixin	[55]
HMG-CoA reductase Inhibitor	Mevastatin, simvastatin	[55]
Rho kinase inhibitor	Ml-7, Ml-9, fasudil	[55,63,94]
Antifungal/antibacterial	Ketoconazole	[55]
Cathartic/emetic	Emetine	[55]
Opioid antagonists	Levallorphan	[55]
Glucocorticoids	Dexamethasone, hydrocortisone, budesonide, flunisolide	[94]
EGF/ErbB2 inhibitor	PD174265	[94]

PPAR: Peroxisome proliferator activator receptor. COX-2: Cyclooxygenase-2; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; EGF: Epidermal growth factor.

Table 3 Repurposed drug potential for remyelination

Drug	Safety	BBB	In vitro effects	In vivo effects	MS trials	Mechanism
Quetiapine	+	+	+	+	NCT02087631	Atypical antipsychotic
Fasudil	+	NA	+	+		ROCK Inhibitor
Olesoxime	+	+	+	+	NCT01808885	Mitochondrial permeability transition pore modulator
Ibudilast	+	+	+	+	NCT01982942 NCT01910259	Phosphodiesterase PDE4 inhibitor
Simvastatin	+	+	+/-	+/-	NCT00647348	HMG-CoA reductase inhibitor
Lovastatin	+	+	+	+		HMG-CoA reductase inhibitor
Clemastine	+	+	+	+	NCT02040298	Antihistamine
IRX4204	NA	+	+	NA		Retinoid X receptor agonist
Bexarotene	+/-	+	-	-		Retinoid X receptor agonist
Benztropine	+/-	+	+	+		M1/M3 muscarinic receptor antagonist

BBB: Blood brain barrier; ROCK: Rho kinase; NA: Not available; MS: Multiple sclerosis; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A.