Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury

J Ruschel, F Bradke - Experimental neurology, 2018 - Elsevier
J Ruschel, F Bradke
Experimental neurology, 2018Elsevier
Central nervous system (CNS) injuries cause permanent impairments of sensorimotor
functions as mature neurons fail to regenerate their severed axons. The poor intrinsic growth
capacity of adult CNS neurons and the formation of an inhibitory lesion scar are key
impediments to axon regeneration. Systemic administration of the microtubule stabilizing
agent epothilone B promotes axon regeneration and recovery of motor function by activating
the intrinsic axonal growth machinery and by reducing the inhibitory fibrotic lesion scar …
Abstract
Central nervous system (CNS) injuries cause permanent impairments of sensorimotor functions as mature neurons fail to regenerate their severed axons. The poor intrinsic growth capacity of adult CNS neurons and the formation of an inhibitory lesion scar are key impediments to axon regeneration. Systemic administration of the microtubule stabilizing agent epothilone B promotes axon regeneration and recovery of motor function by activating the intrinsic axonal growth machinery and by reducing the inhibitory fibrotic lesion scar. Thus, epothilones hold clinical promise as potential therapeutics for spinal cord injury. Here we tested the efficacy of epothilone D, an epothilone B analog with a superior safety profile. By using liquid chromatography and mass spectrometry (LC/MS), we found adequate CNS penetration and distribution of epothilone D after systemic administration, confirming the suitability of the drug for non-invasive CNS treatment. Systemic administration of epothilone D reduced inhibitory fibrotic scarring, promoted regrowth of injured raphespinal fibers and improved walking function after mid-thoracic spinal cord contusion injury in adult rats. These results confirm that systemic administration of epothilones is a valuable therapeutic strategy for CNS regeneration and repair after injury and provides a further advance for potential clinical translation.
Elsevier