Regeneration and sprouting of chronically injured corticospinal tract fibers in adult rats promoted by NT-3 and the mAb IN-1, which neutralizes myelin-associated neurite growth inhibitors.

Abstract

Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery.