Microtubule stabilization promoted axonal regeneration and functional recovery after spinal root avulsion

Abstract

A spinal root avulsion injury disconnects spinal roots with the spinal cord. The rampant motoneuron death, inhibitory CNS/PNS transitional zone (TZ) for axonal regrowth and limited regeneration speed together lead to motor dysfunction. Microtubules rearrange to assemble a new growth cone and disorganized microtubules underline regeneration failure. It has been shown that microtubule-stabilizing drug, Epothilone B, enhanced axonal regeneration and attenuated fibrotic scaring after spinal cord injury. Here, we are reporting that after spinal root avulsion+ re-implantation in adult rats, EpoB treatment improved motor functional recovery and potentiated electrical responses of motor units. It facilitated axons to cross the TZ and promoted more and bigger axons in the peripheral nerve. Neuromuscular junctions were reformed with better preserved postsynaptic structure, and muscle atrophy was prevented by EpoB administration. Our study showed that EpoB was a promising therapy for promoting axonal regeneration after peripheral nerve injury.

Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair

“…Our in-depth evaluation of the mechanism of action of DTX in axonal regeneration demonstrated that DTX regulated the dynamic rearrangement and stabilization of microtubules, which are essential for axonal outgrowth 60 , 61 , by improving the expression of Ace-tubulin and increasing the A/T ratio. DTX also strengthened and improved the motility of the growth cone, as revealed by the increasing intensity of F-actin staining, and thus elongated the microtubules by regulating the forces imposed on the microtubules by molecular motor proteins 47 , 62 , 63 . DTX further disentangled the coupled interaction of microtubules and F-actin, which facilitated further polymerization and stabilization of the overall cytoskeleton structure in the growth cone and filopodial extensions.…”

Epothilone D accelerates disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

“…Pharmacological targeting of microtubules has become a popular and attractive approach to increase microtubule stability and integrity in various neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, tauopathies and schizophrenia , including ALS . Administration of low doses of antimitotic compounds that target microtubules can improve pathology and outcomes in various disease models . These doses are generally 30‐fold lower than those used in cancer therapy, where high doses of antimitotic compounds prevent cellular proliferation and promote cellular apoptosis.…”

Targeting microtubules in axonal re‐ and degeneration (Commentary on Li et al. ())

“…Stabilizing microtubules could thus be a common approach to heal microtubule disturbances occurring in these various conditions, but the question arises as to what to use for this purpose. The most intensely studied microtubule‐stabilizing drug is paclitaxel (taxol); however, in contrast to paclitaxel and most other taxanes, EpoD and selected congeners are brain‐penetrant: an essential requirement for a therapeutic candidate designed to influence axon regrowth after avulsion at the CNS/PNS transitional zone as used by Li and Wu (). Other studies have shown that brain‐penetrant microtubule‐stabilizing drugs such as EpoD or dictyostatin reduce axonal dysfunction and improve cognition in mouse models of tauopathy (Zhang et al ., ; Makani et al ., ).…”

“…Thus, potentially harmful side effects might limit the use of general microtubule stabilizers during long‐term treatment, as would be required for the therapy of AD or PD. The use of microtubule stabilizers as a potential treatment for acute conditions such as spinal root avulsion caused by accidents as described in the paper by Li & Wu () may have a greater chance to be of benefit for the patients.…”

“…The injury involves both the central nervous (CNS) and peripheral nervous system (PNS), and a particular complication is directed axon regrowth of the affected motor neurons through the inhibitory CNS/PNS transitional zone. Li & Wu () employ a rat avulsion model to analyse potential therapeutic options to treat spinal root avulsion injury by targeting microtubules. They used systemic administration of the microtubule‐stabilizing drug, epothilone B (EpoB), to support the microtubule system.…”