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Pyrimidine Derivative Ameliorates Spinal Cord Injury via Anti-apoptotic, Anti-inflammatory, and Antioxidant Effects and by Regulating Rho GTPases

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Abstract

One of the most important strategies for the treatment of spinal cord injury is searching for new and effective pharmacological neuroprotectors and regeneration stimulators. The derivatives of pyrimidine are universal stimulators of the regeneration of various tissues as they support the recovery of nervous structures. The protective effect of the cocrystal of 1,2-dihydro-4,6-dimethyl-1-(2-hydroxyethyl)-pyrimidinone-2 with para-aminobenzoic acid (compound conjugate III, CCIII) was explored on a rat model with a contusion spinal cord injury. Injection of CCIII significantly reduced the expression of tumor necrosis factor α (TNF-α), inhibited the synthesis of myeloperoxidase (MPO), matrix metalloproteinase 9 (MPP9), cyclooxygenase-2 (COX2), and macrophage marker CD68, and increased the level of superoxide dismutase 1 (SOD1). Additionally, the expression of caspase-7 markers in the damaged tissue decreased under the action of CCIII. Treatment with the CCIII maintained a population of Olig2-positive myelin-forming cells at 30 days post-injury. The detected therapeutic effect is comparable with that of riluzole.

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Acknowledgements

We would like to thank D. N. Fattakhova, Kazan State Medical University (Kazan, Russia) for their assistance in some experiments.

Funding

This work was funded by grant №14-50-00014 from the Russian Science Foundation and supported by Program of Competitive Growth of KFU.

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Authors and Affiliations

  1. Kazan Federal University, 18 Kremlyovskaya Street, Kazan, Tatarstan Republic, Russia, 420008

    Tatyana V. Povysheva & Yuri A. Chelyshev

  2. Kazan State Medical University, 49 Butlerova Street, Kazan, Tatarstan Republic, Russia, 420012

    Tatyana V. Povysheva, Syumbel R. Sabirova & Yuri A. Chelyshev

  3. A.E. Arbuzov Institute of Organic and Physical Chemistry Kazan Scientific Center, Russian Academy of Science, 8 Arbuzov Street, Kazan, Tatarstan Republic, Russia, 420088

    Michael S. Shashin, Irina V. Galyametdinova & Vyacheslav E. Semenov

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  1. Tatyana V. Povysheva
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Correspondence to Tatyana V. Povysheva.

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Povysheva, T.V., Sabirova, S.R., Shashin, M.S. et al. Pyrimidine Derivative Ameliorates Spinal Cord Injury via Anti-apoptotic, Anti-inflammatory, and Antioxidant Effects and by Regulating Rho GTPases. BioNanoSci. 9, 224–234 (2019). https://doi.org/10.1007/s12668-018-0570-z

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