A Remyelinating Agent for Treatment of Multiple Sclerosis

Background: Multiple Sclerosis (MS) is a most disabling autoimmune neurological disorder characterized by inflammation, demyelination and axonal damage in the CNS that is caused by irregular invasion of peripheral immune cells into the brain. While currently marketed MS drugs address the immune/inflammatory arm of the disease, none of them demonstrate activities in repairing the damage to the myelin sheath or to the axon. NeuroRepai℞ has developed a series of neuropeptides including a lead compound NRx112, with potent anti-inflammatory and novel reparative activities both in vitro and in vivo. Our previous study showed that NRx112 could promote functional recovery and reduce pathological damage, i.e., demyelination in the spinal cords of animal model of MS.

Objectives: In order to investigate if NRx112 supports remyelination in the brain, several in vivo and in vitro demyelination models were used. 

Methods: One of the most common animal model of demyelination in the CNS is the cuprizone model. Feeding C57 mice with cuprizone diet for 6 weeks induces almost complete demyelination in the corpus callosum of the brain. After withdrawal of the cuprizone diet, NRx112 (4 mg/kg) or vehicle and negative peptide controls was administrated by subcutaneous injection three times a week for 4 weeks.

Results:  We find that treatment with NRx112 resulted in significantly improved remyelination in the corpus callosum region compared to vehicle or negative peptide controls. Electron microscopic analysis confirmed that NRx112 treatment increased the density of myelinated fibers and the thickness of myelin sheath in the corpus callosum. Furthermore, the number of myelinating cell oligodendrocytes in the corpus callosum is higher in NRx112 treated animals than controls. Consistently, using an in vitro demyelination model induced by lysolecithin in rat pup cerebellar slice cultures, we found that post-treatment with NRx112 also significantly elevated the level of myelin basic protein (MBP) by Western blotting, indicating a remyelination-promoting effect of NRx112. In addition, we find that NRx112 also stimulates axon elongation and reverses the inhibition of myelin debris or Nogo-A on axon outgrowth in primary neuronal cultures.

Conclusions: These data support the idea that NRx112 possesses anti-inflammatory, remyelination-/neuroregeneration-promoting activities. The combination of these favorable properties is most desirable for the treatment of MS patients that may potentially restore their lost functions more effectively than current treatments.