Table 1 Overview of molecules for potential therapeutic use 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. |