Midkine overcomes neurite outgrowth inhibition of chondroitin sulfate proteoglycan without glial activation and promotes functional recovery after spinal cord injury

Injuries in the mammalian central nervous system induce a variety of factors which promote or inhibit neuronal axon regeneration/sprouting. However, the inhibitory activities are much stronger, and indeed are the major obstacle to functional recovery. Chondroitin sulfate proteoglycans (CSPGs) are produced by activated glial cells, and are among the strongest inhibitors. Here, we investigated the role of the growth factor midkine (MK), which binds to CSPGs, in neuronal injury. MK expression was induced by spinal cord injury, and was mainly produced by activated astrocytes. A prolonged culture of neurons also produced MK. MK not only enhanced neurite outgrowth on the substratum coated with poly-l-lysine, but also overcame the neurite growth inhibition by the CSPG substratum. Moreover, we found that MK activated neither astrocytes nor microglia as evaluated by morphological changes and cell proliferation or nitric oxide production. These properties would be advantageous for the treatment of neuronal injuries in vivo. Therefore, we next explored the therapeutic effect of MK in a rat spinal cord injury model. MK or vehicle was administered intrathecally for 2 weeks using an osmotic pump after spinal cord contusion injury. Rats treated with MK showed significantly better functional recovery after 5 weeks. These results suggest that MK may offer a potent alternative for the treatment of neuronal injuries without activating glial cells.