The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

TLDR

Spinal axons do not regenerate spontaneously, but elevating cAMP in neurons before axotomy can promote growth, although prophylactic cAMP injection is ineffective as therapy. Rolipram, a PDE4 inhibitor that crosses the blood–brain barrier, promotes axonal regeneration, reduces reactive gliosis, and improves motor function after spinal cord injury when delivered subcutaneously for 10 days, making it a promising post‑injury therapy.

Abstract

Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood–brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo . Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.