Abstract
BackgroundInhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.Methodology/Principal FindingsA focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time.Conclusions/SignificanceOur results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.
Highlights
Myelin associated inhibitory factors, including NogoA [1], myelin associated glycoprotein (MAG) [2] and oligodendrocyte myelin glycoprotein (OMgp) [3] are among the major factors known to inhibit regeneration in the CNS [4]
While the focus of most of these studies has addressed the inhibitory roles of Nogo receptor (NgR) or its ligands in axonal regeneration either in EAE demyelinating models [16,19,20] or non-demyelinating conditions [17,21,22], less is known about the roles of myelin inhibitory factors in demyelination condition in which the axons are intact or not targeted
The observed distribution of labled siRNA indicated that IC10 vectorizes siRNA in to cells expressing markers characteristic of NSC and transient amplifying progenitor cells (TAPs) in the adult subventricular zone (SVZ) [37]
Summary
Myelin associated inhibitory factors, including NogoA [1], myelin associated glycoprotein (MAG) [2] and oligodendrocyte myelin glycoprotein (OMgp) [3] are among the major factors known to inhibit regeneration in the CNS [4] These factors bind to a common receptor called Nogo receptor 1 (NgR1) [5]. Since it is well documented that myelin can protect axonal integrity and loss of myelin results in axonal loss and disability [23,24,25,26], it is important to better understand the role of myelin-derived inhibitory factors on myelin repair itself This information is more pertinent given that NgR and its ligands are expressed in demyelinating lesions of MS tissues [9]. We investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm
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