Abstract
Current treatments in multiple sclerosis (MS) are modulating the inflammatory component of the disease, but no drugs are currently available to repair lesions. Our study identifies in MS patients the overexpression of Plexin‐A1, the signalling receptor of the oligodendrocyte inhibitor Semaphorin 3A. Using a novel type of peptidic antagonist, we showed the possibility to counteract the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro when antagonizing Plexin‐A1. The use of this compound in vivo demonstrated a myelin protective effect as shown with DTI‐MRI and confirmed at the histological level in the mouse cuprizone model of induced demyelination/remyelination. This effect correlated with locomotor performances fully preserved in chronically treated animals. The administration of the peptide also showed protective effects, leading to a reduced severity of demyelination in the context of experimental autoimmune encephalitis (EAE). Hence, the disruption of the inhibitory microenvironmental molecular barriers allows normal myelinating cells to exert their spontaneous remyelinating capacity. This opens unprecedented therapeutic opportunity for patients suffering a disease for which no curative options are yet available.
Highlights
The efficient propagation of electrical nerve impulses requires the establishment of myelin sheaths around axons (Baumann & PhamDinh, 2001)
Previous studies showed the expression of Sema3A in Multiple sclerosis (MS) lesions (Williams et al, 2007) where it is supposed to contribute to the lack of remyelination
We examined whether OL express the Sema3A signalling receptor Plexin-A1
Summary
The efficient propagation of electrical nerve impulses requires the establishment of myelin sheaths around axons (Baumann & PhamDinh, 2001). Precursors of oligodendrocytes (OL), the myelinating cells of the central nervous system (CNS), use guidance cues to migrate towards their target neuronal cells This process is not restricted to developmental phases and occurs to a certain extent in the adult brain. Combinations of soluble factors and membrane-bound cues are considered to create a specific molecular environment dictating the precise recognition process leading to the myelination of axons (Piaton et al, 2010) Among these factors regulating the early phase of myelination, members of the Semaphorin family have been shown to regulate OL precursor cell migration in the optic nerve (Tsai & Miller, 2002) and inhibit adult OL process outgrowth (Ricard et al, 2001). Our results suggest a therapeutic potential of inhibiting Plexin-A1 in myelin diseases such as multiple sclerosis in which we found overexpression of Plexin-A1
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