Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury
Open accessAbstract
Microtubule stabilization through epothilones is a promising preclinical therapy for functional recovery following spinal cord injury that stimulates axon regeneration, reduces growth-inhibitory molecule deposition and promotes functional improvements. Rehabilitation therapy is the only clinically validated approach to promote functional improvements following spinal cord injury. However, whether microtubule stabilization can augment the beneficial effects of rehabilitation therapy or act in concert with it to further promote repair remains unknown. Here, we investigated the pharmacokinetic, histological and functional efficacies of epothilone D, epothilone B and ixabepilone alone or in combination with rehabilitation following a moderate contusive spinal cord injury. Pharmacokinetic analysis revealed that ixabepilone only weakly crossed the blood-brain barrier and was subsequently excluded from further investigations. In contrast, epothilones B and D rapidly distributed to CNS compartments displaying similar profiles after either subcutaneous or intraperitoneal injections. Following injury and subcutaneous administration of epothilone B or D, rats were subjected to 7 weeks of sequential bipedal and quadrupedal training. For all outcome measures, epothilone B was efficacious compared with epothilone D. Specifically, epothilone B decreased fibrotic scaring which was associated with a retention of fibronectin localized to perivascular cells in sections distal to the lesion. This corresponded to a decreased number of cells present within the intralesional space, resulting in less axons within the lesion. Instead, epothilone B increased serotonergic fibre regeneration and vesicular glutamate transporter 1 expression caudal to the lesion, which was not affected by rehabilitation. Multiparametric behavioural analyses consisting of open-field locomotor scoring, horizontal ladder, catwalk gait analysis and hindlimb kinematics revealed that rehabilitation and epothilone B both improved several aspects of locomotion. Specifically, rehabilitation improved open-field locomotor and ladder scores, as well as improving the gait parameters of limb coupling, limb support, stride length and limb speed; epothilone B improved these same gait parameters but also hindlimb kinematic profiles. Functional improvements by epothilone B and rehabilitation acted complementarily on gait parameters leading to an enhanced recovery in the combination group. As a result, principal component analysis of gait showed the greatest improvement in the epothilone B plus rehabilitation group. Thus, these results support the combination of epothilone B with rehabilitation in a clinical setting.
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Griffin et al. (2023) compared intraperitoneal versus subcutaneous injections and found greater concentrations of the drug in the brain with subcutaneous injections.
“(Griffin et al., 2023) compared with the effectiveness of intraperitoneal versus subcutaneous injections and found greater concentrations of the drug in the brain with subcutaneous injections.”
From Microtubule-stabilizer epothilone B delays anesthetic-induced unconsciousness in rats (2024) · cites this paper as Griffin et al., 2023
Griffin et al. measured brain concentrations of epoB over time and found sustained levels of epoB in the brain through the 16 d period of their measurements.
“Those authors also measured brain concentrations of epoB over time and found sustained levels of epoB in the brain through the 16 d period of their measurements.”
From Microtubule-stabilizer epothilone B delays anesthetic-induced unconsciousness in rats (2024) · cites this paper as Griffin et al., 2023
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“Three days post-injury, perivascular cells proliferate, migrate and aggregate in the injured area where fibronectin and laminin are assembled at the lesion centre,(40) a response attributed to perivascular type A pericytes.(42) Previous work showed that the effect of epoB at reducing laminin is stronger 4 days post-in…”
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Sorted by citations
Microtubule-stabilizer epothilone B delays anesthetic-induced unconsciousness in rats
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- Authors
- Griffin, J. M., Hingorani Jai Prakash, S., Bockemühl, T., Benner, J. M., Schaffran, B., Moreno-Manzano, V., Büschges, A., & Bradke, F.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe (CIPF) , Valencia 46012 , Spain
- University of Cologne (DE)
- Corresponding author
- Griffin, Jarred M
- Bradke, Frank
- Venue
- Brain Communications
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-12-29
- Volume
- 5
- Issue
- 1
- Pages
- fcad005-fcad005
- ISSN
- 2632-1297 (ISSN-L)
- PMC
- PMC9893225
- OpenAlex
- W4315929144
- Cited by
- 19
- References
- 70
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 2
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- DZNE Pub (submittedVersion, cc-by)
- RiuNet (Universitat Politècnica de València) (submittedVersion, cc-by-nc-nd)
- Funders
- The International Foundation for Research in Paraplegia
- The German Research Foundation
- ERANET AXON REPAIR, ERANET RATER SCI (PDI2021-1243590B-I00/ERDF)
- Spanish Ministry of Science and Innovation
- Spanish State Research Agency
- European Regional Development Fund
- Nordrhein-Westfalen
- ImmunoSensation2
- DFG Collaborative Research Centers (SFB1451)
- Research Training Group 1960 (RTG1960)
- DFG/National Science Foundation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Keywords
- spinal cord injury, epothilone B, epothilone D, ixabepilone, microtubule stabilization, rehabilitation, locomotor recovery, gait analysis, axon regeneration, VGLUT1, fibrosis, fibronectin, combination therapy
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