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Table 1 Overview of molecules for potential therapeutic use in MS

From: An unmet clinical need: roads to remyelination in MS

Molecule Mode of action Effect Experimental evidence BBB penetration Clinical use
Klotho (membrane-bound protein) Co-receptor of FGFR responsible for FGF23 signaling Regulation of PTH and vitamin D homeostasis Immunoprecipitation No data available
Cleaved Klotho (ectodomain of the Klotho protein) Modulation of the Wnt and insulin/IGF1 pathways
Phosphorylation of FRS2, ERK and Akt
Activation of mTOR
Promotion of OPC maturation
Acceleration of remyelination
Cuprizone-mediated demyelination animal model
Knock-out animal model
Smo (membrane-bound protein) Activation of the Shh pathway Acceleration of remyelination Primary oligodendrocyte cell culture No data available
Clobetasol (synthetic glucocorticoid) Smo agonist Acceleration of remyelination Cerebellar cultures
MOG35–55 chronic progressive EAE animal model
PLP139–151 relapsing remitting EAE animal model
NMO animal model
+ Treatment of skin disorders (e.g. eczema, psoriasis)
MYRF (transcription factor) Activation of myelin gene promotors Promotion of OPC maturation
Acceleration of remyelination
Knock-out animal model
Lysolecithin animal model
Human tissue analysis
No data available
Anti-RGMa (antibody) Neutralization of the proinflammatory and anti-regenerative molecule RGMa
Reduction of T cell proliferation
Reduction of proinflammatory cytokine secretion
Clinical improvement of EAE
Inhibition of inflammation
Promotion of neuroregeneration
Reduction of proinflammatory microglia
MOG35–55 chronic progressive EAE animal model
PLP139–151 relapsing remitting EAE animal model
NOD secondary progressive EAE animal model
NMO animal model
Human tissue analysis
No data available Phase 2 clinical trials assessing the anti-RGMa-antibody elezanumab in patients with relapsing (NCT03737851) and progressive MS (NCT03737812)
miR146a (endogenous microRNA) Inactivation of IRAK1 Promotion of OPC maturation
Acceleration of remyelination
Cuprizone-mediated demyelination animal model No data available
AS-2P (ascorbic acid derivate) Co-factor of hypoxia-inducible factor (HIF)
Mediation of ubiquitination and proteasomal degradation of hypoxia-inducible factor α (HIF-α)
Antioxidant properties
Promotion of OPC maturation Mouse neural progenitor-derived OPC cell culture
Mouse OPC-dorsal root ganglion neuron coculture
Cuprizone-mediated demyelination animal model
No data available (No penetration of ascorbic acid. Only oxidized form can be transported by GLUT1) Use in the cosmetic industry as AS-2P salts
Tβ4 (hormone-like peptide) Upregulation of p38MAPK and ILK
Anti-inflammatory and immunomodulatory properties
Promotion of OPC proliferation and differentiation
Acceleration of remyelination
Immortalized murine N20.1 oligodendrocyte cell culture
PLP139–151 relapsing remitting EAE animal model
Cuprizone-mediated demyelination animal model
Human tissue analysis
(+) Several phase 1 and phase 2 clinical trials assessing the use in patients with dry eye syndrome (NCT02974907, NCT01393132), ulcers (NCT00382174), epidermolysis bullosa (NCT00311766), myocardial infarction (NCT01311518)
Etazolate (pyrazolopyridine derivative) Alpha-secretase-induced release of the neuroprotective soluble N-terminal APP fragment (sAPPalpha)
GABAA receptor modulator
Alpha-secretase activator
Adenosine antagonist
Promotion of OPC maturation
Acceleration of remyelination
Protection of myelinated axons from demyelination
Cuprizone animal model
Ex vivo lysolecithin-induced demyelination model using cerebellar slices
(+) Phase 2 clinical trial assessing use in patients with Alzheimer’s disease (NCT00880412)
Nimodipine (calcium channel blocker) Inhibition of carnitine palmitoyltransferase 1A (Cpt1a) and NADPH oxidase 4 (Nox4)
Reduction of reactive nitrogen and oxygen species
Induction of microglial apoptosis
Acceleration of remyelination Mouse primary and N9 microglia cell culture
MOG35–55 chronic progressive EAE animal model
PLP139–151 relapsing remitting EAE animal model
MP4-induced EAE animal model
+ Treatment of vasospasm following subarachnoid hemorrhage
Hesperidin (flavonoid) Reduction of proinflammatory cell infiltration into the CNS
T-cell polarization of proinflammatory CD4+ T-cells to a regulatory T cell status
Antioxidant properties
Reduction of inflammation and demyelination MOG35–55 chronic progressive EAE animal model + OTC dietary supplement
Hesperetin (flavonoid) Downregulation of TLR4
Antioxidant properties
Reduction of inflammation and demyelination HT22 neuronal and BV-2 microglial cell culture
Aβ mouse model
Lysolecithin-induced demyelination animal model
+ OTC dietary supplement
Quercetin (flavonoid) Modulation of the Wnt pathway
Release of neurotrophic factors
Attenuation of glutamate-mediated excitotoxicity
Inhibition of NF-κB and reduction of reactive nitrogen species
Reduction of inflammation and demyelination
Acceleration of remyelination
Stimulation of neurite outgrowth
Parental PC12 pheochromozytoma and BV-2 microglial cell culture
Behavioral and neurochemical studies in swiss albino mice
Intracerebral hemorrhage rat model
Ethidium bromide-mediated demyelination animal model
Lysolecithin-induced demyelination animal model
+ OTC dietary supplement
TDP6 (peptide) Mimetic of the neurotrophin BDNF
Activation of TrkB receptors and downstream Erk1/2
Promotion of OPC differentiation
Acceleration of remyelination
Chick and rat primary dorsal root ganglion neuron cell cultures
Primary OPC culture
Mouse/rat OPC-dorsal root ganglion neuron coculture
Cuprizone-mediated demyelination animal model
No data available
Anti-NogoA (antibody) Neutralization of the axonal inhibitory protein Nogo A Promotion of OPC proliferation and differentiation
Acceleration of remyelination
Axonal regeneration
Rat, mouse and monkey spinal cord injury animal models
Rat stroke animal model
MOG35–55 chronic progressive EAE animal model
Lysolecithin-induced demyelination animal model
No data available* Phase 1 clinical trials assessing the use of anti-NogoA-antibody ozanezumab in patients with MS (NCT01435993, NCT01424423). Phase 1 clinical trial assessing the use of anti-NogoA-antibody ATI355 in patients with spinal cord injury (NCT00406016). Phase 1 and phase 2 clinical trial assessing the use anti-NogoA-antibody ozanezumab in amyotrophic lateral sclerosis (NCT00875446, NCT01753076).
Yhhu4952 (quinazoline derivate) Inhibition of the Jagged1-Notch1 pathway Promotion of OPC proliferation and differentiation
Acceleration of remyelination
Rat primary OPC-astrocyte coculture
MOG35–55 chronic progressive EAE animal model
Cuprizone-mediated demyelination animal model
+
Tamoxifen (estrogen receptor modulator) Modulation of estrogen receptors ERα, ERβ, and GPR30 Promotion of OPC differentiation
Acceleration of remyelination
Primary OPC culture
Ethidium bromide-mediated demyelination animal model
+ Breast cancer treatment
CDP-choline (choline metabolite) Possible interaction with members of the ERK/MAPK family Promotion of OPC proliferation
Acceleration of remyelination
Primary OPC, microglial and macrophage cell culture
MOG35–55 chronic progressive EAE animal model
Cuprizone-mediated demyelination animal model
+ OTC dietary supplement
Several clinical trials assessing the use in patients with acute stroke (e.g. NCT00331890), traumatic brain injury (e.g. NCT00545662) or psychiatric disorders (e.g. NCT00223236) among others.
  1. BBB Blood brain barrier, MS Multiple sclerosis, OPC Oligodendroglial precursor cell, PTH Parathyroid hormone, MOG Myelin oligodendrocyte glycoprotein, PLP Proteolipid protein, EAE Experimental autoimmune encephalomyelitis, NMO Neuromyelitis optica, MP4 MBP-PLP fusion protein, NOD Non-obese diabetes, OTC Over the counter, + = penetrates the blood brain barrier, (+) = only little evidence for BBB penetration or low permeability, − = does not penetrate the blood brain barrier, * = Anti-NogoA antibody was administered intravenously in clinical trials with MS patients, but pharmacokinetic data was not publicly accessible