PKC inhibits myelin repair in the context of local demyelination induced in mice optic chiasm

Pourabdolhossein F1, Javan M1, Dehghan S1, Mozafari S1, Mirnajafizadeh J1, Demeneix BA2
1

Tarbiat Modares University, Tehran, Iran; 2Musum National d'Histoire Naturelle, Paris, France

Axon regeneration in adult CNS is limited by the presence of inhibitory proteins associated with myelin. Although blocking Protein Kinase C (PKC) activity attenuates the ability of CNS myelin to inhibit neurite outgrowth, the role as well as mechanisms underlying the remyelination inhibition in CNS are still largely unknown. The identification of neural stem cells (NSCs) in the adult rodent and human CNS opens new perspective for the repair of brain damage. Considering the role of PKC in axonal regeneration and the vulnerability of optic chiasm in multiple sclerosis (MS), we assessed the effect of PKC inhibition on the migration potential of NSCs in response to local demyelination of optic chiasm. The optic chiasm was first demyelinated with 1% LPC (lysophosphatidyl choline). The PKC inhibitor G6976 was daily ICV injected for 14 days. NSCs tracing was done by BrdU labeling and double staining against BrdU and specific marker like Olig2, PSA-NCAM or GFAP to identify different types of progenitors. LPC treatment, Without PKC inhibitor resulted in marked demyelination at days 3 and 7 with incomplete remyelination occurring at days 14. In the presence of PKC inhibitor, weaker demyelination was observed at day 3 and enhanced remyelination as soon as day 7. Tracing studies showed that the number of positive cells at the site of lesion was increased over time, while decreased in the subventricular zone of lateral and third ventricles. PKC inhibition significantly increased the number of double labeled cells in the site of lesion. Our results indicate that PKC inhibition potentiates the migration of NSCs of ventricle pools in response to local demyelination of optic chiasm. PKC-dependent mechanisms normally operate to regulate myelination of CNS axons. Inhibition of PKC activity could represent a potential therapeutic candidate for stimulating the remyelination process in the context of MS.
Keywords: Demyelination, Lysolecithin, NSCs, PKC inhibitor, MS, Mice