NOGO blockade promotes remyelination

Pourabdolhossein F, Mozafari S, Morvan-Dubois G, Mirnajafi-Zadeh J, Lopez-Juarez A, Pierre-Simons J, Demeneix BA, Javan M. Nogo Receptor Inhibition Enhances Functional Recovery following Lysolecithin-Induced Demyelination in Mouse Optic Chiasm. PLoS One. 2014; 9:e106378

BACKGROUND: Inhibitory 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 FINDINGS: A 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, A long latency visual evoked potential is a measure of demyelination. They shine a light in the eye and measure the electrical activity in the brain. In demyelination this is slower so has a longer latency). 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.
CONCLUSIONS/SIGNIFICANCE: Our 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.
Reticulon-4, also known as Neurite outgrowth inhibitor or Nogo is a protein that is an inhibitor of neurite outgrowth specific to the central nervous system. that may also help block the regeneration of the central nervous system. There are three isoforms: Nogo A, B and C. Nogo-A has two known inhibitory domains including amino-Nogo, at the N-terminus and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in growth cone destruction. 

Leucine rich repeat and Ig domain containing 1 also known as LINGO-1 and has been implicated in the inhibition of axon regeneration through a complex formed with NgR1 (ligand-binding subunit) and p75 (signal transducing subunit). The inhibitory action is achieved through RhoAGTP upregulation in response to the presence of  MOG, MAG or Nogo-66 in the central nervous system. LINGO-1 also inhibits oligodendrocyte precursor differentiation and myelination. 

In this study they removed NOGO by blocking the production of the protein using shorty interfering RNA (siRNA) which competes for the messenger RNA that produces the NOGO protein. This promoted growth (assessed by the incorporation of Bromodeoxyuridine. This is incorprorated into the DNA during replication and can be be stained to show the deviding cells) of oligodendrocytes and remyelination in an optic nerve demyelination model and this caused there to be better function of the nerve.

Will this be useful for MS….probably not because it is unlikely that siRNA are going to be used in MS as you need to pump them into the brain. However it says make a drug that inhibits NOGO. A number of companies have done just that and the typical approach has been to make inhibitory antibodies. However will they be any good….On first thought I would have said no because antibodies do not penetrate the central nervous system very well. 

However one company is doing just this with a blocker of LINGO-1 and this is in trial in MS. I guess they hope that the few % of the drug that gets injected gets into the brain is enough. 

If it works the scrabble for a synthetic chemical drug that gets in the brain will occur because there must be better alternatives to antibodies, however if it fails, will the idea just get canned and no one will look for the chemical drug….

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