Abstract
Localized carrier-mediated administration of drugs is a promising approach to treatment of acute phase of spinal cord injury (SCI) as it allows enhanced and/or sustained drug delivery to damaged tissues along with minimization of systemic side effects. We studied the effect of locally applied self-assembling micellar formulation of methylprednisolone succinate (MPS) with trifunctional block copolymer of ethylene oxide and propylene oxide (TBC) on functional recovery and tissue drug content after SCI in rats in comparison with local and systemic administration of MPS alone. Variations in the amplitude of motor evoked responses in the hindlimb muscles induced by epidural stimulation during acute phase of SCI and restoration of movements during chronic period after local vs. systemic application of MPS were evaluated in this study. Results demonstrate that local delivery of MPS in combination with TBC facilitates spinal cord sensorimotor circuitry, increasing the excitability. In addition, this formulation was found to be more effective in improvement of locomotion after SCI compared to systemic administration. LC–MS/MS data shows that the use of TBC carrier increases the glucocorticoid content in treated spinal cord by more than four times over other modes of treatment. The results of this study demonstrate that the local treatment of acute SCI with MPS in the form of mixed micelles with TBC can provide improved therapeutic outcome by promoting drug accumulation and functional restoration of the spinal cord.
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Acknowledgements
The study was supported by the Russian Foundation for Basic Research (Project No. 18-315-00267 mol_a, Baltin M.), and T.A. Abdullin acknowledges Russian Science Foundation project No 20-14-00166 (preparation of amphiphilic polymer and micellar formulation). The work was performed according to the Program of competitive growth of Kazan Federal University (KFU). The equipment of Interdisciplinary Centre for Shared Use of KFU was used. Alexander Laikov (KFU) is greatly acknowledged for LC–MS/MS analysis. In 2020, the study was funded by the subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities, project No 0671-2020-0059.
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All the authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MB, DS and NA. Conceptualization: IL and TB. Methodology: electrophysiology: EIK; synthesis of substances and mass spectrometry: TA, MK and NP. Formal analysis and investigation: OS. Writing—review and editing: TB, MB. The first draft of the manuscript was written by MB, which is his dissertation material, and all the authors commented on previous versions of the manuscript. All the authors have read and approved the final manuscript.
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Baltin, M.E., Sabirova, D.E., Kiseleva, E.I. et al. Comparison of systemic and localized carrier-mediated delivery of methylprednisolone succinate for treatment of acute spinal cord injury. Exp Brain Res 239, 627–638 (2021). https://doi.org/10.1007/s00221-020-05974-w
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DOI: https://doi.org/10.1007/s00221-020-05974-w