Nogo Receptor Inhibition Enhances Functional Recovery following Lysolecithin-Induced Demyelination in Mouse Optic Chiasm

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.

Stem Cell Therapy: A Promising Therapeutic Approach for Multiple Sclerosis

“…Xu and others reported that the third ventricle ependymal layer cells were able to migrate into hypothalamic parenchymal regions and differentiate into functional neurons in response to injury (172). Our previous study also showed that progenitor cells in the third ventricle surroundings could be reactivated by local demyelination in the optic chiasm (128,171). Also nestin and DCX-positive cells have been found in the meninges of the brain and spinal cord (138,173).…”

“…Certain antidepressants like fluoxetine have been revealed to be capable of increasing neurogenesis (203). Administration of small interfering RNA (siRNA) or specific antibodies against various inhibitory targets such as Nogo, Nogo receptor (NgR), LINGO1, and Sema3A in different animal models of MS and spinal cord injury enhance proliferation, migration, and differentiation potential of endogenous stem cells and facilitate axonal regeneration, myelin repair, and functional recovery (128,(204)(205)(206)(207). Khezri and coworkers reported that administration of cyclic AMP inhibits the progression of EAE disease and potentiates recruitment of endogenous NSCs and myelin repair (208).…”

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

“…12,18,19 VEP has been used in animal models to assess neurological or potential eff ects on remyelination of the adenosine A1 receptor agonist N6-cyclohexyladenosine and siRNAs against the Nogo receptor. 20,21 VEP was also used in single or small multicentre clinical studies assessing high-dose intravenous immunoglobulin, erythropoietin, simvastatin, and phenytoin in patients with acute optic neuritis, [22][23][24][25] and in natural recovery observational studies after an acute optic neuritis episode. 12,16,17,[26][27][28] When baseline characteristics of participants enrolled in RENEW were compared with those in trials of other candidate remyelinating or neuroprotective drugs, age and percentage of women were similar, mean number of days from fi rst acute optic neuritis symptom to fi rst dose was 24 days in RENEW versus 5-20 days in previous acute optic neuritis studies.…”

The axon–glia unit in white matter stroke: Mechanisms of damage and recovery

“…Recent reports have indicated that NogoA plays a direct role in regulating myelination in vitro and in an in vivo model of focal demyelination (Chong et al, 2012). Furthermore, blocking NgR1 significantly enhanced the remyelination process, recruitment of proliferating OPC to the lesion site, and functional recovery after demyelination in the optic nerve (Pourabdolhossein et al, 2014). The mechanism for NgR1-mediated inhibition of neurite outgrowth involves activation of RhoA and its downstream effector Rho kinase ROCK (Niederost et al, 2002), however, whether this mechanism also plays a role in the regulation of OPC and remyelination is still unknown.…”