Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor

Abstract

The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery promoted by epoB. The same SCI model treated by epoB was established as discussed previously. We used a cerebrospinal fluid (CSF) sample to assess the changes in cytokines in milieu of the SCI lesion site after epoB treatment. We then analyzed the source of cytokines, the state of microglia/macrophages/monocytes (M/Ms), and the recruitment of neutrophil in the lesion site by using the results of antibody array. Following these findings, we further evaluated the motor functional recovery caused by the reshaped microenvironment. Systemic administration of epoB significantly increased levels of several cytokines in the CSF of the rat SCI model; macrophage colony-stimulating factor (M-CSF) secreted by intact central nervous system (CNS) cells was one of the cytokines with increased levels. Along with epoB and other cytokines, M-CSF reshapes the SCI milieu by activating the microglias, killing bone marrow-derived macrophages, polarizing the M/M to M1 phenotype, and activating downstream cytokines to exacerbate the SCI injury, but it also increases the expression of neurotrophic factors. Anti-inflammatory therapy using a neutralizing antibody mix shows encouraging results. Using in vivo experiments, our findings indicate that epoB inhibits the SCI functional recovery in many ways by reshaping the milieu, which counteracts the therapeutic efficacy that led to the limited overall effectiveness.

Knockdown of Fidgetin Improves Regeneration of Injured Axons by a Microtubule-Based Mechanism

“…However, an independent attempt failed to achieve notable regeneration or functional recovery, with only modest improvements apparently attributable to the effects of the drugs on non-neuronal cells contributing to the glial scar (Popovich et al, 2014). Other recent studies suggest that epothilones can actually be detrimental to functional recovery from spinal cord injury (Mao et al, 2017). To whatever degree that benefits may occur and through whatever mechanism, concern nevertheless exists about introducing microtubule-stabilizing drugs into the CNS, especially given the severe side effects of taxol treatment on peripheral nerves in patients taking the drug as cancer therapy (Scripture et al, 2006;Fukuda et al, 2017).…”

Epothilone B Benefits Nigral Dopaminergic Neurons by Attenuating Microglia Activation in the 6-Hydroxydopamine Lesion Mouse Model of Parkinson’s Disease

“…Instead of inducing apoptosis in tumor cells at therapeutic doses, subtoxic concentrations of EpoB have been shown to promote regeneration of axons and suppress formation of the glia scar in spinal cord injury models (Ruschel et al, 2015 ). Besides its microtubule stability function, EpoB was confirmed to have an immunoregulation function such as increasing the secretion of macrophage colony-stimulating factor (M-CSF) during regeneration in spinal cord injury (Mao et al, 2017 ). Inflammation has been recognized as playing an important role in the pathogenesis of PD (Kannarkat et al, 2013 ).…”

Polycaprolactone electrospun fiber scaffold loaded with iPSCs-NSCs and ASCs as a novel tissue engineering scaffold for the treatment of spinal cord injury

“…7 The microenvironment of the spinal cord changes immediately after a mechanical crushing or stretching of the spinal cord. [8][9][10] Axonal damage and cell membrane disruption cause glia loss in the primary injury of the spinal cord. 11 Then, a cascade of molecular and signaling pathways initiate a series of secondary injuries to the spinal cord.…”