On the mechanisms of the synergistic action of tolperisone, meloxicam and B vitamins in the treatment of peripheral pain syndromes

Introduction: The combined use of non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants and group B vitamins is a promising direction for combined pharmacotherapy of peripheral pain syndromes.

Purpose: to analyze the molecular mechanisms of the synergism of the muscle relaxant tolperisone, a non-steroidal anti-inflammatory drug meloxicam and vitamins B₁, B₆ and B₁₂ as part of complex pharmacotherapy of pain.

Materials and methods: differential chemoreactome analysis of NSAID molecules and muscle relaxants, proteomic analysis of the effects of B vitamins.

Results: Synergistic interactions are maintained by (1) inhibiting cyclooxygenase-2 and leukotriene A4 hydrolases; (2) inhibition of the effects of IL-1β, TNFα, NF-kB, TLR4, RANKL, matrix metalloproteinases; (3) antioxidant effect (increased expression of superoxide dismutase-1 and glutathione peroxidase). Group B vitamins enhance the effects of tolperisone and meloxicam due to the manifestation of independent anti-inflammatory (neutralization of homocysteine, decreased expression of pro-inflammatory cytokines TNFα, IL-1b and factor NF-kB activity), analgesic (modulation of opioidergic pathways) and neuroprotective effects (support of amino acid expression, metabolism and neuro lipids, ATP synthesis and remyelination).

Conclusions: The triple scheme “tolperisone + meloxicam + vitamins B₁ / B₆ / B₁₂” is characterized by a number of undeniable advantages: (1) lack of dependence, (2) anti-inflammatory effect, (3) neuroprotective and remyelinating effects, (4) elimination of muscle hypertonicity. Such combination therapy can be used in patients of various age groups with comorbid conditions (diabetes mellitus, arterial hypertension, cerebrovascular diseases, gastrointestinal diseases) and does not require an increase in NSAIDs and significantly reduces the risk of side effects.

1. Parfenov V.A., Yakhno N.N., Kukushkin M.L., Churyukanov M.V., Davydov O.S., Golovacheva V.A. et al. Acute nonspecific (musculoskeletal) low back pain Guidelines of the Russian Society for the Study of Pain (RSSP). Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(2):4–11. (In Russ.) doi: 10.14412/2074-2711-2018-2-4-11.

2. Putilina M.V. Vertebrogenic back pain: Current Potentials For Treatment. Pharmateca. 2012;(7):95–99. (In Russ.) Available at: https://pharmateca.ru/en/archive/article/8155.

3. Mozolevsky Yu.V., Barinov A.N. Combination treatment for tunnel neuropathies of the lower extremities. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2013;(4):10–20. (In Russ.) doi: 10.14412/2074-2711-2013-2449.

4. Barinov A.N. Entrapment neuropathies: rationale for pathogenetic therapy. Vrach = Doctor. 2012;(4):31–37. (In Russ.) Available at: http://neuro.rusvrach.ru/ru/vrach-2012-04-07.

5. Mumenthaler M., Stöhr M., Müller-Vahl H. (eds.). Läsionen peripherer Nerven und radikuläre Syndrome. Stuttgart: Georg Thieme Verlag; 2007. 501 p.

6. Andreev A.V., Gromova O.A., Skoromets A.A. The use of mido-calm blockades in the treatment of spondylo-genic lumbar pain syndromes. Results of thedouble-blind study. RMZH = RMJ. 2002;(21):968–972. (In Russ.) Available at: https://www.rmj.ru/articles/nevrologiya/Primenenie_midokalmovyh_blokad_v_lechenii_spondilogennyh_poyasnichnyh_bolevyh_sindromov_Rezulytaty_dvoynogo_slepogo_issledovaniya.

7. Fischoff D., Spivakovsky S. Are pharmaco-logical treatments for oro-facial pain effective? Evid Based Dent. 2018;19(1):28–29. doi: 10.1038/sj.ebd.6401294.

8. Torshin I.Y., Gromova O.A., Stakhovskaya L.V., Semenov V.A. Chemoreactome analysis of tolperisone, tizanidine, and baclofen molecules: anticholinergic, antispasmodic, and analgesic mechanisms of action. Nevrologiya, neyropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(4):72–80. (In Russ.) doi: 10.14412/2074-2711-2018-4-72-80.

9. Gromova O.A., Torshin I.Yu., Prokopovich O.A. Synergistic neuroprotective effects of thiamine, pyridoxine and cyanocobalamin within the human proteome. Nevrologiya i revmatologiya. Prilozhenie k zhurnalu Consilium Medicum = Neurology and rheumatology. Appendix to the journal Consilium Medicum. 2016;(2):76–84. (In Russ.) Available at: https://www.elibrary.ru/item.asp?id=29187690.

10. Torshin I.Y., Gromova O.A., Stakhovskaya L.V., Semenov V.A., Gromov A.N. Differential chemoreactome analysis of synergistic combinations of tolperisone and nonsteroidal anti-inflammatory drugs. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2019;11(2):78–85. (In Russ.) doi: 10.14412/2074-2711-2019-2-78-85.

11. Midttun O., Hustad S., Schneede J., Vollset S.E., Ueland P.M. Plasma vitamin B-6 forms and their relation to transsulfuration metabolites in a large, populationbased study. Am J Clin Nutr. 2007;86(1):131–138. doi: 10.1093/ajcn/86.1.131.

12. Bettendorff L., Wins P., Lesourd M. Subcellular localization and compartmentation of thiamine derivatives in rat brain. Biochim Biophys Acta. 1994;1222(1):1–6. doi: 10.1016/0167-4889(94)90018-3.

13. Fournier H., Butterworth R.F. Effects of maternal thiamine deficiency on the development of thiamine-dependent enzymes in regions of the rat brain. Neurochem Int. 1989;15(4):439–444. doi: 10.1016/0197-0186(89)90162-9.

14. Kimura S., Ohtuki N., Nezu A., Tanaka M., Takeshita S. Clinical and radiologic improvements in mitochondrial encephalomyelopathy following sodium dichloroacetate therapy. Brain Dev. 1997;19(8):535–540. doi: 10.1016/s0387-7604(97)00074-0.

15. Sterzel R.B., Semar M., Lonergan E.T., Treser G., Lange K. Relationship of nervous tissue transketolase to the neuropathy in chronic uremia. J Clin Invest. 1971;50(11):2295–2304. doi: 10.1172/JCI106727.

16. Lu’o’ng K.V., Nguyen L.T. Thiamine and Parkinson’s disease. J Neurol Sci. 2012;316(1–2):1–8. doi: 10.1016/j.jns.2012.02.008.

17. Karuppagounder S.S., Xu H., Shi Q., Chen L.H., Pedrini S., Pechman D. et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiol Aging. 2009;30(10):1587–1600. doi: 10.1016/j.neurobiolaging.2007.12.013.

18. Neri M., Cantatore S., Pomara C., Riezzo I., Bello S., Turillazzi E., Fineschi V. Immunohistochemical expression of proinflammatory cytokines IL-1beta, IL-6, TNF-alpha and involvement of COX-2, quantitatively confirmed by Western blot analysis, in Wernicke’s encephalopathy. Pathol Res Pract. 2011;207(10):652–658. doi: 10.1016/j.prp.2011.07.005.

19. Jhala S.S., Wang D., Hazell A.S. Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes. Biochem Biophys Res Commun. 2014;448(3):335–341. doi: 10.1016/j.bbrc.2014.04.017.

20. Zhang H., Peng A.L., Zhao F.F., Yu L.H., Wang M.Z., Osorio J.S., Wang H.R. Thiamine ameliorates inflammation of the ruminal epithelium of Saanen goats suffering from subacute ruminal acidosis. J Dairy Sci. 2020;103(2):1931–1943. doi: 10.3168/jds.2019-16944.

21. Pavlov D., Gorlova A., Bettendorff L., Kalueff A.A., Umriukhin A., Proshin A. et al. Enhanced conditioning of adverse memories in the mouse modified swim test is associated with neuroinflammatory changes – effects that are susceptible to antidepressants. Neurobiol Learn Mem. 2020;172:107227. doi: 10.1016/j.nlm.2020.107227.

22. Roomi M.W., Ishaque A., Khan N.R., Eylar E.H. Glycoproteins and albumin in peripheral nerve myelin. J Neurochem. 1978;31(1):375–379. doi: 10.1111/j.1471-4159.1978.tb12476.x.

23. Michailova M., Keita Y., Caspary S., Solem E., Kratzer W., Worner G., Rietbrock N. Inhibitory effect of vitamin B6 on nonenzymatic glycation of albumin and hemoglobin. Int J Clin Pharmacol Ther Toxicol. 1992;30(11):547–548.

24. Oka T., Komori N., Kuwahata M., Okada M., Natori Y. Vitamin B6 modulates expression of albumin gene by inactivating tissue-specific DNA-binding protein in rat liver. Biochem J. 1995;309(1):243–248. doi: 10.1042/bj3090243.

25. Isola L.M., Zhou S.L., Kiang C.L., Stump D.D., Bradbury M.W., Berk P.D. 3T3 fibroblasts transfected with a cDNA for mitochondrial aspartate aminotransferase express plasma membrane fatty acid-binding protein and saturable fatty acid uptake. Proc Natl Acad Sci U S A. 1995;92(21):9866–9870. doi: 10.1073/pnas.92.21.9866.

26. Almeida M.R., Mabasa L., Crane C., Park C.S., Venancio V.P., Bianchi M.L., Antunes L.M. Maternal vitamin B6 deficient or supplemented diets on expression of genes related to GABAergic, serotonergic, or glutamatergic pathways in hippocampus of rat dams and their offspring. Mol Nutr Food Res. 2016;60(7):1615–1624. doi: 10.1002/mnfr.201500950.

27. Rai N.K., Ashok A., Rai A., Tripathi S., Nagar G.K., Mitra K., Bandyopadhyay S. Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina. Toxicol Appl Pharmacol. 2013;273(2):242–258. doi: 10.1016/j.taap.2013.05.003.

28. Castegna A., Palmieri L., Spera I., Porcelli V., Palmieri F., Fabis-Pedrini M.J. et al. Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience. 2011;185:97–105. doi: 10.1016/j.neuroscience.2011.04.041.

29. Swanson K.V., Deng M., Ting J.P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–489. doi: 10.1038/s41577-019-0165-0.

30. Zhang P., Tsuchiya K., Kinoshita T., Kushiyama H., Suidasari S., Hatakeyama M. et al. Vitamin B6 Prevents IL-1beta Protein Production by Inhibiting NLRP3 Inflammasome Activation. J Biol Chem. 2016;291(47):24517–24527. doi: 10.1074/jbc.M116.743815.

31. Sanada Y., Kumoto T., Suehiro H., Nishimura F., Kato N., Hata Y., Sorisky A., Yanaka N. RASSF6 expression in adipocytes is down-regulated by interaction with macrophages. PLoS One. 2013;8(4):e61931. doi: 10.1371/journal.pone.0061931.

32. Selhub J., Byun A., Liu Z., Mason J.B., Bronson R.T., Crott J.W. Dietary vitamin B6 intake modulates colonic inflammation in the IL10-/- model of inflam matory bowel disease. J Nutr Biochem. 2013;24(12):2138–2143. doi: 10.1016/j.jnutbio.2013.08.005.

33. Chang H.Y., Tang F.Y., Chen D.Y., Chih H.M., Huang S.T., Cheng H.D. et al. Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism. Am J Clin Nutr. 2013;98(6):1440–1449. doi: 10.3945/ajcn.113.064477.

34. Buesing S., Costa M., Schilling J.M., Moeller-Bertram T. Vitamin B12 as a Treatment for Pain. Pain Physician. 2019;22(1):45–52. Available at: https://pubmed.ncbi.nlm.nih.gov/11558625.

35. Erfanparast A., Escort M., Tamaddonfard E., Maroufi S., Kazemi-Shojaei S., Dabbaghi M., Taati M. Systemic and local peripheral injections of vitamin B12 suppressed orofacial nociception induced by formalin in rats. Drug Res (Stuttg). 2014;64(2):85–90. doi: 10.1055/s-0033-1353164.

36. Xu J., Wang W., Zhong X.X., Feng Y., Wei X., Liu X.G. EXPRESS: Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats: Effect on loss of peripheral nerve fibers and imbalance of cytokines in the spinal dorsal horn. Mol Pain. 2016;12. doi: 10.1177/1744806916657089.

37. Sampaio A.L., Dalli J., Brancaleone V., D’Acquisto F., Perretti M., Wheatley C. Biphasic modulation of NOS expression, protein and nitrite products by hydroxocobalamin underlies its protective effect in endotoxemic shock: downstream regulation of COX-2, IL-1beta, TNF-alpha, IL-6, and HMGB1 expression. Mediators Inflamm. 2013;2013:741–804. doi: 10.1155/2013/741804.

38. Tamaddonfard E., Tamaddonfard S., Cheraghiyan S. Effects of intracerebroventricular injection of vitamin B12 on formalin-induced muscle pain in rats: Role of cyclooxygenase pathway and opioid receptors. Vet Res Forum. 2018;9(4):329–335. doi: 10.30466/vrf.2018.33104.

39. Jurna I. Analgesic and analgesia-potentiating action of B vitamins. Schmerz. 1998;12(2):136–141. doi: 10.1007/s004829800054.

40. Sudduth T.L., Powell D.K., Smith C.D., Greenstein A., Wilcock D.M. Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. J Cereb Blood Flow Metab. 2013;33(5):708–715. doi: 10.1038/jcbfm.2013.1.

41. Hofmann M.A., Lalla E., Lu Y., Gleason M.R., Wolf B.M., Tanji N. et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107(6):675–683. doi: 10.1172/JCI10588.

42. Zhang X., Chen S., Li L., Wang Q., Le W. Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. Neuropharmacology. 2008;54(7):1112–1119. doi: 10.1016/j.neuropharm.2008.02.020.

43. Samblas M., Martinez J.A., Milagro F. Folic Acid Improves the Inflammatory Response in LPS-Activated THP-1 Macrophages. Mediators Inflamm. 2018;2018:1312626. doi: 10.1155/2018/1312626.

44. Wang T., Zhang T., Sun L., Li W., Zhang C., Yu L., Guan Y. Gestational B-vitamin supplementation alleviates PM2.5-induced autism-like behavior and hippocampal neurodevelopmental impairment in mice offspring. Ecotoxicol Environ Saf. 2019;185:109–686. doi: 10.1016/j.ecoenv.2019.109686.

45. Nenseter M.S., Ueland T., Retterstol K., Strom E., Morkrid L., Landaas S. et al. Dysregulated RANK ligand/RANK axis in hyperhomocysteinemic subjects: effect of treatment with B-vitamins. Stroke. 2009;40(1):241–247. doi: 10.1161/STROKEAHA.108.522995.

46. Gromova O.A., Torshin I.Ju., Filimonova M.V., Sorokina M.A. The role of vitamins in cancerprevention and their influence at anticancer treatment efficacy: systematic analysis of evidentaryresearch works. Terapiya = Therapy. 2018;(4):108–120. (In Russ.) Available at: https://therapy-journal.ru/ru/archive/article/36479.

47. Gromova O.A., Stakhovskaya L.V., Torshin I.Yu., Filimonova M.V., Kovrazhkina E.A. On the antitumor potential of vitamin B12. Rossiyskiy zhurnal boli = Russian Journal of Pain. 2017;(2):62–73. (In Russ.) Available at: https://medi.ru/info/13514.

48. Gromova O.A., Torshin I.Yu. Micronutrients and reproductive health. Moscow: GEOTAR-Media; 2019. 672 p. (In Russ.)

49. Mechanic A.G. Artificial intelligence on guard of health. The first conversation with O.A. Thundering and I.Yu. Torshin. Stimul: Zhurnal ob innovatsiyakh v Rossii = Stimulus: Journal of Innovation in Russia. 2019. (In Russ.) Available at: https://stimul.online/articles/science-and-technology/iskusstvennyy-intellekt-na-strazhe-zdorovya-beseda-pervaya/.

50. Gromova O.A., Torshin I.Yu., Frolova D.E., Filimonova M.V. Antitumor effects of the combined use of vitamins B1, B6 and B12. Nevrologiya i Revmatologiya (Prilozhenie k zhurnalu Consilium Medicum) = Neurology and Rheumatology (Appendix to the journal. Consilium Medicum). 2018;(1):62–66. (In Russ.) doi: 10.26442/2414-357X_2018.1.62-66.