Epothilone B Facilitates Peripheral Nerve Regeneration by Promoting Autophagy and Migration in Schwann Cells

Abstract

The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years. Epothilone B (EpoB) is an FDA-approved antineoplastic agent, which shows the capacity to induce α-tubulin polymerization and to improve the stability of microtubules. Recently, it has been increasingly recognized that EpoB has a regenerative effect in the central nervous system. However, the information currently available regarding the potential therapeutic effect of EpoB on peripheral nerve regeneration is limited. Here, we used a rat sciatic crush injury model system to determine that EpoB strikingly improved axonal regeneration and recovery of function. Also, EpoB (1 nM) did not result in significant apoptosis in Schwann cells (SCs) and showed little effect on their viability either. Interestingly, EpoB (1 nM) significantly enhanced migration in SCs, which was inhibited by autophagy inhibitors 3-methyladenine (3-MA). Since PI3K/Akt signaling has been implicated in regulating autophagy, we further examined the involvement of PI3K/Akt in the process of EpoB-induced SC migration. We found that EpoB (1 nM) significantly inhibited phosphorylation of PI3K and Akt in SCs. Further studies showed that both EpoB-enhanced migration and autophagy were increased/inhibited by inhibition/activation of PI3K/Akt signaling with LY294002 or IGF-1. In conclusion, EpoB can promote axonal regeneration following peripheral nerve injury by enhancing the migration of SCs, with this activity being controlled by PI3K/Akt signaling-mediated autophagy in SCs. This underscores the potential therapeutic value of EpoB in enhancing regeneration and functional recovery in cases of peripheral nerve injury.

Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury

“…Many studies have shown that paclitaxel promotes axonal regeneration after central nervous system injury (Hellal et al, 2011;Sengottuvel et al, 2011;Austin et al, 2017). In addition, epothilone B, another microtubule-stabilizing agent, facilitates peripheral nerve regeneration (Zhou et al, 2020). Similar to these earlier studies, the present study illustrates that paclitaxel treatment significantly enhances morphologic and functional recovery in the injured sciatic nerve and its target muscles.…”

“…While a few studies have investigated the effects of microtubule-stabilizing agents on PNI, the results are contradictory. For example, Hsu et al (2017) reported that paclitaxel impairs nerve regeneration in a rat model of sciatic nerve transection, while Zhou et al (2020) found that epothilone B, another U.S. Food and Drug Administration-approved microtubule-stabilizing agent, facilitates peripheral nerve regeneration. To our knowledge, the current study is the first to describe the role of microtubule dynamics in WD, and the first to explore the effects of both a microtubule-stabilizing agent (paclitaxel) and a microtubuledestabilizing agent (nocodazole) on PNI repair.…”

Aligned Fingolimod-Releasing Electrospun Fibers Increase Dorsal Root Ganglia Neurite Extension and Decrease Schwann Cell Expression of Promyelinating Factors

“…To investigate the effect of fingolimod-releasing fibers on Schwann cell phenotype, we first measured Schwann cell migration distance outward from the whole DRG body. This assessment is important when investigating the regenerative potential of a material for the PNS because the migration of Schwann cells can stimulate greater axon extension (Torigoe et al, 1996;Zhou et al, 2020). Schwann cell migration was significantly greater on all fingolimod-releasing fiber scaffolds compared with the control fibers, with the greatest increase observed on the 0.02% fingolimod-loaded fibers.…”

Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche

“…Excessive autophagy induced by oxidative stress leads to the death of Schwann cells, whereas docosahexaenoic acid (DHA) attenuates this phenomenon ( Tatsumi et al, 2022 ). In contrast, epothilone B (EpoB) promotes axonal regeneration following peripheral nerve injury by promoting PI3K/Akt signaling-mediated autophagy in Schwann cells and enhancing migration ( Zhou et al, 2020 ). Moreover, autophagy in Schwann cells, which can be activated by nerve growth factor, is crucial for myelin debris clearance to expedite nerve regeneration following peripheral nerve injury ( Li et al, 2020 ).…”