Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

Abstract

BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.

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

“…It is noteworthy that intraperitoneal administration of low doses of epothilone suppressed axonal microtubule loss and alleviated cognitive defects in a mouse model of tauopathy (Ballatore et al, 2012 ), and systemic injection of epothilone D was neuroprotective in an MPTP-induced mouse model of parkinsonism (Cartelli et al, 2013 ). Recently, we demonstrated that EpoB alleviated injury of the nigrostriatal pathway after intracerebral hemorrhage and improved motor function in a mouse model (Yang et al, 2018a ), confirming the neuroprotective effects of EpoB.…”

“…The beam walking test was performed to assess motor coordination and was conducted according to previously described methods (Yang et al, 2018a ). A beam of 6 mm width, 1.2 m length and 60 cm height was used in this study.…”

“…To mimic the activated state of microglia in PD in vivo (Keren-Shaul et al, 2017 ; Krasemann et al, 2017 ), mixed culture of MN9D cells and BV2 cells was then treated with 50 μM 6-OHDA for 24 h (Xi et al, 2017 ; Zhang et al, 2017 ). After this stimulation, cells were washed twice with PBS, and then treated with EpoB (5 nmol/L) for another 12 h (Yang et al, 2018a ). BV2 cells were collected for immunofluorescence detection, western blot analysis and real-time polymerase chain reaction (RT-PCR) test, and MN9D cells were collected for apoptosis analysis (Figure 1B ).…”

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

“…Epothilones act similarly but are preferred because they cross the blood-brain barrier (Ruschel et al, 2015). In a plethora of studies published over the past several years, microtubule-stabilizing drugs have been shown to augment nerve regeneration in the culture dish as well as animal models, even leading to partial recovery of function in rats with injured spinal cords (Hellal et al, 2011;Sengottuvel et al, 2011;Ruschel et al, 2015;Li et al, 2017;Ruschel and Bradke, 2018;Sandner et al, 2018;Yang et al, 2018;Yin et al, 2018). 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).…”

Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage

“…The study design is shown in Figure 1(a). The ICH model was established in accordance with previously described methods as shown in Figure 1(b) [15]. Mice were anesthetized with isoflurane (3% for induction and 1-1.5% for maintenance).…”