Brief research report: Repurposing pentoxifylline to treat intense acute swimming-Induced delayed-onset muscle soreness in mice: Targeting peripheral and spinal cord nociceptive mechanisms
Sergio M Borghi, Tiago H Zaninelli, Telma Saraiva-Santos, Mariana M Bertozzi, Renato D R Cardoso, Thacyana T Carvalho, Camila R Ferraz, Doumit Camilios-Neto, Fernando Q Cunha, Thiago M Cunha, Felipe A Pinho-Ribeiro, Rubia Casagrande, Waldiceu A Verri Jr, Sergio M Borghi, Tiago H Zaninelli, Telma Saraiva-Santos, Mariana M Bertozzi, Renato D R Cardoso, Thacyana T Carvalho, Camila R Ferraz, Doumit Camilios-Neto, Fernando Q Cunha, Thiago M Cunha, Felipe A Pinho-Ribeiro, Rubia Casagrande, Waldiceu A Verri Jr
Abstract
In this study, we pursue determining the effect of pentoxifylline (Ptx) in delayed-onset muscle soreness (DOMS) triggered by exposing untrained mice to intense acute swimming exercise (120 min), which, to our knowledge, has not been investigated. Ptx treatment (1.5, 4.5, and 13.5 mg/kg; i.p., 30 min before and 12 h after the session) reduced intense acute swimming-induced mechanical hyperalgesia in a dose-dependent manner. The selected dose of Ptx (4.5 mg/kg) inhibited recruitment of neutrophils to the muscle tissue, oxidative stress, and both pro- and anti-inflammatory cytokine production in the soleus muscle and spinal cord. Furthermore, Ptx treatment also reduced spinal cord glial cell activation. In conclusion, Ptx reduces pain by targeting peripheral and spinal cord mechanisms of DOMS.
Keywords: cytokine; glial cells; muscle mechanical hyperalgesia; oxidative stress; pentoxifylline.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Copyright © 2023 Borghi, Zaninelli, Saraiva-Santos, Bertozzi, Cardoso, Carvalho, Ferraz, Camilios-Neto, Cunha, Cunha, Pinho-Ribeiro, Casagrande and Verri.
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References
- Alvarez P., Bogen O., Green P. G., Levine J. D. (2017). Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat. Pain 158, 1481–1488. 10.1097/j.pain.0000000000000936
- Aoi W., Naito Y., Takanami Y., Kawai Y., Sakuma K., Ichikawa H., et al. (2004). Oxidative stress and delayed-onset muscle damage after exercise. Free Radic. Biol. Med. 37, 480–487. 10.1016/j.freeradbiomed.2004.05.008
- Armstrong R. B. (1984). Mechanisms of exercise-induced delayed onset muscular soreness: A brief review. Med. Sci. Sports Exerc 16, 529–538. 10.1249/00005768-198412000-00002
- Baird M. F., Graham S. M., Baker J. S., Bickerstaff G. F. (2012). Creatine-kinase- and exercise-related muscle damage implications for muscle performance and recovery. J. Nutr. Metab. 2012, 960363. 10.1155/2012/960363
- Bas D. B., Su J., Sandor K., Agalave N. M., Lundberg J., Codeluppi S., et al. (2012). Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum. 64, 3886–3896. 10.1002/art.37686
- Basbaum A. I., Bautista D. M., Scherrer G., Julius D. (2009). Cellular and molecular mechanisms of pain. Cell 139, 267–284. 10.1016/j.cell.2009.09.028
- Bhat V. B., Madyastha K. M. (2001). Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline. Biochem. Biophys. Res. Commun. 288, 1212–1217. 10.1006/bbrc.2001.5922
- Blair N. T., Bean B. P. (2002). Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci. 22, 10277–10290. 10.1523/JNEUROSCI.22-23-10277.2002
- Borghi S. M., Bussulo S. K. D., Pinho-Ribeiro F. A., Fattori V., Carvalho T. T., Rasquel-Oliveira F. S., et al. (2021). Intense acute swimming induces delayed-onset muscle soreness dependent on spinal cord neuroinflammation. Front. Pharmacol. 12, 734091. 10.3389/fphar.2021.734091
- Borghi S. M., Pinho-Ribeiro F. A., Fattori V., Bussmann A. J., Vignoli J. A., Camilios-Neto D., et al. (2016). Quercetin inhibits peripheral and spinal cord nociceptive mechanisms to reduce intense acute swimming-induced muscle pain in mice. PLoS One 11, e0162267. 10.1371/journal.pone.0162267
- Borghi S. M., Pinho-Ribeiro F. A., Zarpelon A. C., Cunha T. M., Alves-Filho J. C., Ferreira S. H., et al. (2015). Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice. Exp. Physiol. 100, 531–544. 10.1113/EP085026
- Borghi S. M., Zarpelon A. C., Pinho-Ribeiro F. A., Cardoso R. D., Cunha T. M., Alves-Filho J. C., et al. (2014a). Targeting interleukin-1β reduces intense acute swimming-induced muscle mechanical hyperalgesia in mice. J. Pharm. Pharmacol. 66, 1009–1020. 10.1111/jphp.12226
- Borghi S. M., Zarpelon A. C., Pinho-Ribeiro F. A., Cardoso R. D., Martins-Pinge M. C., Tatakihara R. I., et al. (2014b). Role of TNF-α/TNFR1 in intense acute swimming-induced delayed onset muscle soreness in mice. Physiol. Behav. 128, 277–287. 10.1016/j.physbeh.2014.01.023
- Bourgeois J., Macdougall D., Macdonald J., Tarnopolsky M. (1999). Naproxen does not alter indices of muscle damage in resistance-exercise trained men. Med. Sci. Sports Exerc 31, 4–9. 10.1097/00005768-199901000-00002
- Broderick C., Forster R., Abdel-Hadi M., Salhiyyah K. (2020). Pentoxifylline for intermittent claudication. Cochrane Database Syst. Rev. 10, CD005262. 10.1002/14651858.CD005262.pub4
- Bussulo S. K. D., Ferraz C. R., Carvalho T. T., Verri W. A., Jr., Borghi S. M. (2021). Redox interactions of immune cells and muscle in the regulation of exercise-induced pain and analgesia: Implications on the modulation of muscle nociceptor sensory neurons. Free Radic. Res. 55, 757–775. 10.1080/10715762.2021.1953696
- Carvalho T. T., Borghi S. M., Pinho-Ribeiro F. A., Mizokami S. S., Cunha T. M., Ferreira S. H., et al. (2015). Granulocyte-colony stimulating factor (G-CSF)-induced mechanical hyperalgesia in mice: Role for peripheral TNFα, IL-1β and IL-10. Eur. J. Pharmacol. 749, 62–72. 10.1016/j.ejphar.2014.12.023
- Chao C. C., Hu S., Close K., Choi C. S., Molitor T. W., Novick W. J., et al. (1992). Cytokine release from microglia: Differential inhibition by pentoxifylline and dexamethasone. J. Infect. Dis. 166, 847–853. 10.1093/infdis/166.4.847
- Cheung K., Hume P., Maxwell L. (2003). Delayed onset muscle soreness: Treatment strategies and performance factors. Sports Med. 33, 145–164. 10.2165/00007256-200333020-00005
- Clark A. K., Malcangio M. (2012). Microglial signalling mechanisms: Cathepsin S and fractalkine. Exp. Neurol. 234, 283–292. 10.1016/j.expneurol.2011.09.012
- Connolly D. A., Sayers S. P., Mchugh M. P. (2003). Treatment and prevention of delayed onset muscle soreness. J. Strength Cond. Res. 17, 197–208. 10.1519/1533-4287(2003)017<0197:tapodo>;2
- Cunha T. M., Verri W. A., Jr., Schivo I. R., Napimoga M. H., Parada C. A., Poole S., et al. (2008). Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. J. Leukoc. Biol. 83, 824–832. 10.1189/jlb.0907654
- Doherty G. M., Jensen J. C., Alexander H. R., Buresh C. M., Norton J. A. (1991). Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110, 192–198.
- Dorazil-Dudzik M., Mika J., Schafer M. K., Li Y., Obara I., Wordliczek J., et al. (2004). The effects of local pentoxifylline and propentofylline treatment on formalin-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw. Anesth. Analg. 98, 1566–1573. 10.1213/01.ane.0000113235.88534.48
- Dos Santos R. S., Veras F. P., Ferreira D. W., Sant'anna M. B., Lollo P. C. B., Cunha T. M., et al. (2020). Involvement of the Hsp70/TLR4/IL-6 and TNF-alpha pathways in delayed-onset muscle soreness. J. Neurochem. 155, 29–44. 10.1111/jnc.15006
- Drobnic F., Riera J., Appendino G., Togni S., Franceschi F., Valle X., et al. (2014). Reduction of delayed onset muscle soreness by a novel curcumin delivery system (Meriva®): A randomised, placebo-controlled trial. J. Int. Soc. Sports Nutr. 11, 31. 10.1186/1550-2783-11-31
- Eun B. L., Liu X. H., Barks J. D. (2000). Pentoxifylline attenuates hypoxic-ischemic brain injury in immature rats. Pediatr. Res. 47, 73–78. 10.1203/00006450-200001000-00014
- Fantin M., Quintieri L., Kusz E., Kis E., Glavinas H., Floreani M., et al. (2006). Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties. Eur. J. Pharmacol. 535, 301–309. 10.1016/j.ejphar.2006.02.017
- Han J., Huez G., Beutler B. (1991). Interactive effects of the tumor necrosis factor promoter and 3'-untranslated regions. J. Immunol. 146, 1843–1848. 10.4049/jimmunol.146.6.1843
- Hotfiel T., Freiwald J., Hoppe M. W., Lutter C., Forst R., Grim C., et al. (2018). Advances in delayed-onset muscle soreness (DOMS): Part I: Pathogenesis and diagnostics. Sportverletz Sportschaden 32, 243–250. 10.1055/a-0753-1884
- Huizinga T. W., Dijkmans B. A., Van Der Velde E. A., Van De Pouw Kraan T. C., Verweij C. L., Breedveld F. C. (1996). An open study of pentoxyfylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis. Ann. Rheum. Dis. 55, 833–836. 10.1136/ard.55.11.833
- Inacio M. D., Costa M. C., Lima T. F. O., Figueiredo I. D., Motta B. P., Spolidorio L. C., et al. (2020). Pentoxifylline mitigates renal glycoxidative stress in obese mice by inhibiting AGE/RAGE signaling and increasing glyoxalase levels. Life Sci. 258, 118196. 10.1016/j.lfs.2020.118196
- Jimenez-Altayo F., Briones A. M., Giraldo J., Planas A. M., Salaices M., Vila E. (2006). Increased superoxide anion production by interleukin-1beta impairs nitric oxide-mediated relaxation in resistance arteries. J. Pharmacol. Exp. Ther. 316, 42–52. 10.1124/jpet.105.088435
- Jin X., Gereau R. W. T. (2006). Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J. Neurosci. 26, 246–255. 10.1523/JNEUROSCI.3858-05.2006
- Kilpatrick L. E., Sun S., Li H., Vary T. C., Korchak H. M. (2010). Regulation of TNF-induced oxygen radical production in human neutrophils: Role of delta-PKC. J. Leukoc. Biol. 87, 153–164. 10.1189/jlb.0408230
- Kim H. K., Hwang S. H., Lee S. O., Kim S. H., Abdi S. (2016). Pentoxifylline ameliorates mechanical hyperalgesia in a rat model of chemotherapy-induced neuropathic pain. Pain Physician 19, E589–E600. 10.36076/ppj/2019.19.e589
- Legendre D. P., Muzny C. A., Swiatlo E. (2012). Hansen's disease (leprosy): Current and future pharmacotherapy and treatment of disease-related immunologic reactions. Pharmacotherapy 32, 27–37. 10.1002/PHAR.1009
- Lima L. V., Abner T. S. S., Sluka K. A. (2017). Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena. J. Physiol. 595, 4141–4150. 10.1113/JP273355
- Liu J., Feng X., Yu M., Xie W., Zhao X., Li W., et al. (2007). Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain. Neurosci. Lett. 412, 268–272. 10.1016/j.neulet.2006.11.022
- Macintyre D. L., Reid W. D., Mckenzie D. C. (1995). Delayed muscle soreness. The inflammatory response to muscle injury and its clinical implications. Sports Med. 20, 24–40. 10.2165/00007256-199520010-00003
- Meamarbashi A., Rajabi A. (2015). Preventive effects of 10-day supplementation with saffron and indomethacin on the delayed-onset muscle soreness. Clin. J. Sport Med. 25, 105–112. 10.1097/JSM.0000000000000113
- Mika J., Osikowicz M., Makuch W., Przewlocka B. (2007). Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur. J. Pharmacol. 560, 142–149. 10.1016/j.ejphar.2007.01.013
- Mika J., Osikowicz M., Rojewska E., Korostynski M., Wawrzczak-Bargiela A., Przewlocki R., et al. (2009). Differential activation of spinal microglial and astroglial cells in a mouse model of peripheral neuropathic pain. Eur. J. Pharmacol. 623, 65–72. 10.1016/j.ejphar.2009.09.030
- Ming W. J., Bersani L., Mantovani A. (1987). Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J. Immunol. 138, 1469–1474. 10.4049/jimmunol.138.5.1469
- Muir W. W. (2009). “Physiology and pathophysiology of pain,” in Handbook of veterinary pain management. Editors Gaynor J. S., Muir W. W. Second ed (Amsterdam, Netherlands: Elsevier; ), 13–42.
- Murase S., Terazawa E., Hirate K., Yamanaka H., Kanda H., Noguchi K., et al. (2013). Upregulated glial cell line-derived neurotrophic factor through cyclooxygenase-2 activation in the muscle is required for mechanical hyperalgesia after exercise in rats. J. Physiol. 591, 3035–3048. 10.1113/jphysiol.2012.249235
- Murase S., Terazawa E., Queme F., Ota H., Matsuda T., Hirate K., et al. (2010). Bradykinin and nerve growth factor play pivotal roles in muscular mechanical hyperalgesia after exercise (delayed-onset muscle soreness). J. Neurosci. 30, 3752–3761. 10.1523/JNEUROSCI.3803-09.2010
- Neuner P., Klosner G., Schauer E., Pourmojib M., Macheiner W., Grunwald C., et al. (1994). Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology 83, 262–267.
- Nicol L. M., Rowlands D. S., Fazakerly R., Kellett J. (2015). Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS). Eur. J. Appl. Physiol. 115, 1769–1777. 10.1007/s00421-015-3152-6
- Pedretti S., Rena C. L., Orellano L. A. A., Lazari M. G., Campos P. P., Nunes T. A. (2020). Benefits of pentoxifylline for skin flap tissue repair in rats. Acta Cir. Bras. 35, e301105. 10.1590/ACB351105
- Pereira B. C., Lucas G., Da Rocha A. L., Pauli J. R., Ropelle E. R., Cintra D., et al. (2015). Eccentric exercise leads to glial activation but not apoptosis in mice spinal cords. Int. J. Sports Med. 36, 378–385. 10.1055/s-0034-1395589
- Pinho-Ribeiro F. A., Verri W. A., Jr., Chiu I. M. (2017). Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19. 10.1016/j.it.2016.10.001
- Price M. L., Lai Y. E., Marcus K. L., Robertson J. B., Lascelles B. D. X., Nolan M. W. (2021). Early radiation-induced oral pain signaling responses are reduced with pentoxifylline treatment. Vet. Radiol. Ultrasound 62, 255–263. 10.1111/vru.12943
- Ruiz-Miyazawa K. W., Pinho-Ribeiro F. A., Borghi S. M., Staurengo-Ferrari L., Fattori V., Amaral F. A., et al. (2018). Hesperidin methylchalcone Suppresses experimental Gout arthritis in mice by inhibiting NF-κB activation. J. Agric. Food Chem. 66, 6269–6280. 10.1021/acs.jafc.8b00959
- Rustay N. R., Wahlsten D., Crabbe J. C. (2003). Assessment of genetic susceptibility to ethanol intoxication in mice. Proc. Natl. Acad. Sci. U. S. A. 100, 2917–2922. 10.1073/pnas.0437273100
- Saito O., Svensson C. I., Buczynski M. W., Wegner K., Hua X. Y., Codeluppi S., et al. (2010). Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br. J. Pharmacol. 160, 1754–1764. 10.1111/j.1476-5381.2010.00811.x
- Sampaio E. P., Moraes M. O., Nery J. A., Santos A. R., Matos H. C., Sarno E. N. (1998). Pentoxifylline decreases in vivo and in vitro tumour necrosis factor-alpha (TNF-alpha) production in lepromatous leprosy patients with erythema nodosum leprosum (ENL). Clin. Exp. Immunol. 111, 300–308. 10.1046/j.1365-2249.1998.00510.x
- Shimodaira T., Mikoshiba S., Taguchi T. (2019). Nonsteroidal anti-inflammatory drugs and acetaminophen ameliorate muscular mechanical hyperalgesia developed after lengthening contractions via cyclooxygenase-2 independent mechanisms in rats. PLoS One 14, e0224809. 10.1371/journal.pone.0224809
- Silva R., Malcangio M. (2021). Fractalkine/CX(3)CR(1) pathway in neuropathic pain: An update. Front. Pain Res. (Lausanne) 2, 684684. 10.3389/fpain.2021.684684
- Singla N., Desjardins P. J., Cosca E. B., Parulan C., Arriaga A., Poole K. C., et al. (2015). Delayed-onset muscle soreness: A pilot study to assess analgesic study design features. Pain 156, 1036–1045. 10.1097/j.pain.0000000000000109
- Souza G. R., Talbot J., Lotufo C. M., Cunha F. Q., Cunha T. M., Ferreira S. H. (2013). Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc. Natl. Acad. Sci. U. S. A. 110, 11193–11198. 10.1073/pnas.1307445110
- Strieter R. M., Remick D. G., Ward P. A., Spengler R. N., Lynch J. P., 3rd, Larrick J., et al. (1988). Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun. 155, 1230–1236. 10.1016/s0006-291x(88)81271-3
- Tarabay B., Komboz F., Kobaiter-Maarrawi S., Fayad F., Zeid H. A., Maarrawi J. (2022). Pentoxifylline significantly reduces radicular pain secondary to lumbar disc hernia: A prospective, randomized crossover, single-blind controlled pilot study. Clin. Neurol. Neurosurg. 219, 107309. 10.1016/j.clineuro.2022.107309
- Vale M. L., Benevides V. M., Sachs D., Brito G. A., Da Rocha F. A., Poole S., et al. (2004). Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain. Br. J. Pharmacol. 143, 833–844. 10.1038/sj.bjp.0705999
- Verghese M. W., Mcconnell R. T., Strickland A. B., Gooding R. C., Stimpson S. A., Yarnall D. P., et al. (1995). Differential regulation of human monocyte-derived TNF alpha and IL-1 beta by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors. J. Pharmacol. Exp. Ther. 272, 1313–1320.
- Verri W. A., Jr., Cunha T. M., Parada C. A., Poole S., Cunha F. Q., Ferreira S. H. (2006). Hypernociceptive role of cytokines and chemokines: Targets for analgesic drug development? Pharmacol. Ther. 112, 116–138. 10.1016/j.pharmthera.2006.04.001
- Vircheva S., Alexandrova A., Georgieva A., Mateeva P., Zamfirova R., Kubera M., et al. (2010). In vivo effects of pentoxifylline on enzyme and non-enzyme antioxidant levels in rat liver after carrageenan-induced paw inflammation. Cell Biochem. Funct. 28, 668–672. 10.1002/cbf.1705
- Wei T., Sabsovich I., Guo T. Z., Shi X., Zhao R., Li W., et al. (2009). Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome. Eur. J. Pain 13, 253–262. 10.1016/j.ejpain.2008.04.014
- Zeng C., Luo G., Xu S., Li Y. (2022). The application of DOMS mechanism and prevention in physical education and training. J. Healthc. Eng. 2022, 9654919. 10.1155/2022/9654919
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