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Daphnetin, a natural coumarin averts reserpine-induced fibromyalgia in mice: modulation of MAO-A

Abstract

Fibromyalgia is a common, chronic, and generalized pain syndrome that is often associated with comorbid depression. The etiology of fibromyalgia is complex; most researchers have documented that the hallmark symptoms are due to the central nervous system’s abnormal functioning. Neurotransmitters such as serotonin, norepinephrine, and glutamate, have been reported to be key regulators of fibromyalgia syndrome. Daphnetin is a 7, 8 dihydroxy coumarin widely distributed in Thymelaeaceae family plants, possessing various activities such as anti-arthritic, anti-tumor, anti-malarial, and anti-parasitic. The present study was designed to explore the potential of daphnetin against reserpine-induced fibromyalgia in mice. In mice, a fibromyalgia-like state was achieved by injecting reserpine (0.5 mg/kg, s.c) continuously for 3 days. All behavioral tests were conducted on the 4th and 6th day of experimentation. Reserpine administration significantly increased the mechanical hypersensitivity in electronic von Frey (eVF) and pressure application measurement (PAM) tests. It also increased the immobility period and time to reach the platform in force swim test (FST) and Morris water maze (MWM) test, respectively. In the biochemical analysis, reserpine treatment upregulated the monoamine oxidase-A (MAO-A) activity and level of glutamate, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and thiobarbituric acid reactive substances (TBARS). Whereas, it decreased the level of glutathione (GSH), dopamine, serotonin, and norepinephrine. Daphnetin pretreatment attenuated the behavioral and biochemical changes induced by reserpine. Thus, the current investigation results delineate that daphnetin might exert its protective effect by inhibiting inflammatory stress and MAO-A-mediated neurotransmitter depletion and oxidative stress.

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Data availability

All data generated or analyzed during this study are included in this article.

Abbreviations

eVF:

Electronic von Frey

PAM:

Pressure application measurement

FST:

Forced swim test

MWM:

Morris water maze

TBARS:

Thiobarbituric acid reactive substances

TNF-α:

Tumor necrosis factor-alpha

IL-1β:

Interleukin-1beta

MAO-A:

Monoamine oxidase-A

GSH:

Reduced glutathione

5-HT:

5-Hydroxytryptamine (serotonin)

CNS:

Central nervous system

SNRIs:

Serotonin–norepinephrine reuptake inhibitors

CMC:

Carboxy methyl cellulose

DTNB:

5-5′-Di-thio-bis [2-nitrobenzoic acid]

TNB:

5-Thio-nitrobenzoic acid

MDA:

Malondialdehyde

References

  1. Altier N, Stewart J (1998) Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. J Pharmacol Exp Ther 2855:208–215

    Google Scholar 

  2. Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr, Welge JA, Bishop F, Stanford KE, Hess EV, Hudson JI (2007) Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum 56:1336–1344

    CAS  PubMed  Google Scholar 

  3. Arora V, Chopra K (2013) Possible involvement of oxido-nitrosative stress induced neuro-inflammatory cascade and monoaminergic pathway: underpinning the correlation between nociceptive and depressive behaviour in a rodent model. J Affect Disord 151:1041–1052

    CAS  PubMed  Google Scholar 

  4. Arora V, Kuhad A, Tiwari V, Chopra K (2011) Curcumin ameliorates reserpine-induced pain–depression dyad: behavioural, biochemical, neurochemical and molecular evidences. Psychoneuroendocrinology 6:1570–1581

    Google Scholar 

  5. Ceko M, Bushnell MC, Gracely RH (2012). Neurobiology underlying fibromyalgia symptoms. Pain Res Treat https://doi.org/10.1155/2012/585419

  6. Chang CC (1964) A sensitive method for spectrophotofluorometric assay of catecholamines. Neuropharmacology 3:643–649

    CAS  Google Scholar 

  7. Clark L, Bechara A, Damasio H, Aitken MR, Sahakian BJ, Robbins TW (2008) Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making. Brain 131:1311–1322

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Clauw DJ, Arnold LM, McCarberg BH (2011) The science of fibromyalgia. Mayo Clin Proc 86:907–911

    PubMed  PubMed Central  Google Scholar 

  9. Cooper TE, Derry S, Wiffen PJ, Moore RA (2017) Gabapentin for fibromyalgia pain in adults. Cochrane Database Syst Rev 1:CD012188

  10. Deuis JR, Dvorakova LS, Vetter I (2017) Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 10:284

    PubMed  PubMed Central  Google Scholar 

  11. Diniz DA, Petrocchi JA, Navarro LC, Souza TC, Castor MG, Duarte ID, Romero TR (2018) Serotonin induces peripheral antinociception via the opioidergic system. Biomed Pharmacother 97:1434–1437

    CAS  PubMed  Google Scholar 

  12. Evans PH (1993) Free radicals in brain metabolism and pathology. Br Med Bull 49:577–587

    CAS  PubMed  Google Scholar 

  13. Fatima G, Mahdi F (2017) Deciphering the role of oxidative and antioxidative parameters and toxic metal ion content in women with fibromyalgia syndrome. Free Radic Biol Med 112:23–24

    Google Scholar 

  14. Friend R, Bennett RM (2011) Distinguishing fibromyalgia from rheumatoid arthritis and systemic lupus in clinical questionnaires: an analysis of the revised fibromyalgia impact questionnaire (FIQR) and its variant, the symptom impact questionnaire (SIQR), along with pain locations. Arthritis Res Ther 13:1–10

    Google Scholar 

  15. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749

    CAS  PubMed  Google Scholar 

  16. Gao Q, Shan J, Di L, Jiang L, Xu H (2008) Therapeutic effects of daphnetin on adjuvant-induced arthritic rats. J Ethnopharmacol 120:259–263

    CAS  PubMed  Google Scholar 

  17. Golan H, Levav T, Mendelsohn A, Huleihel M (2004) Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb Cortex 14:97–105

    CAS  PubMed  Google Scholar 

  18. Gracely RH, Petzke F, Wolf JM, Clauw DJ (2002) Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 46:1333–1343

    PubMed  Google Scholar 

  19. Gracely RH, Ceko M, Bushnell MC (2012) Fibromyalgia and depression. Pain Res Treat. https://doi.org/10.1155/2012/486590

  20. Gursoy S, Erdal E, Sezgin M, Barlas IO, Aydeniz A, Alaşehirli B, Sahin G (2008) Which 21 genotype of the MAO gene that the patients have are likely to be most susceptible to the 22 symptoms of fibromyalgia? Rheumatol Int 28:307–311

    CAS  PubMed  Google Scholar 

  21. Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacol 37:137

    CAS  Google Scholar 

  22. Hasler G (2010) Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry 9:155–161

    PubMed  PubMed Central  Google Scholar 

  23. Himmerich H, Patsalos O, Lichtblau N, Ibrahim MA, Dalton B (2019) Cytokine research in depression: principles, challenges, and open questions. Front Psychiatry 10:30

    PubMed  PubMed Central  Google Scholar 

  24. Kaur A, Singh L, Singh N, Bhatti MS, Bhatti R (2019) Ameliorative effect of imperatorin in chemically induced fibromyalgia: role of NMDA/NFkB mediated downstream signaling. Biochem Pharmacol 166:56–69

    CAS  PubMed  Google Scholar 

  25. Kia S, Choy E (2017) Update on treatment guideline in fibromyalgia syndrome with focus on pharmacology. Biomedicines 5:20

    PubMed Central  Google Scholar 

  26. Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, Wasan AD, Edwards RR, Napadow V (2015) Fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks. NeuroImage Clin 7:667–677

    PubMed  PubMed Central  Google Scholar 

  27. Kitagami T, Yamada K, Miura H, Hashimoto R, Nabeshima T, Ohta T (2003) Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier. Brain Res 978:104–114

    CAS  PubMed  Google Scholar 

  28. Klein CP, Sperotto ND, Maciel IS, Leite CE, Souza AH, Campos MM (2014) Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology 86:57–66

    CAS  PubMed  Google Scholar 

  29. Kranzler JD, Gendreau JF, Rao SG (2002) The psychopharmacology of fibromyalgia: a drug development perspective. Psychopharmacol Bull 36:165–213

    PubMed  Google Scholar 

  30. Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bushnell MC (2007) Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci 27:4004–4007

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lam CS, Li JJ, Tipoe GL, Youdim MB, Fung ML (2017) Monoamine oxidase A upregulated by chronic intermittent hypoxia activates indoleamine 2, 3-dioxygenase and neurodegeneration. PLoS One 12:e0177940

    PubMed  PubMed Central  Google Scholar 

  32. Lichtenstein A, Tiosano S, Amital H (2018) The complexities of fibromyalgia and its comorbidities. Curr Opin Rheumatol 30:94–100

    PubMed  Google Scholar 

  33. Marazziti D, Castrogiovanni P, Rossi A, Rosa C, Ghione S, Di Muro A, Panattoni E, Cassano GB (1998) Pain threshold is reduced in depression. Int J Neuropsychopharmacol 1:45–48

    PubMed  Google Scholar 

  34. Matos MJ, Santana L, Uriarte E, Abreu OA, Molina E, Yordi EG (2015) Coumarins-an important class of phytochemicals. In: Phytochemicals isolation, characterisation and role in human health, vol 30, pp 113–140. https://doi.org/10.5772/59982

  35. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH (2009) The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebocontrolled trial. J Rheumatol 36:398–409

    CAS  PubMed  Google Scholar 

  36. Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, Becerril-Villanueva E, Arreola R, Hernández-Ferreira E, Pérez-Tapia SM, Pérez-Sánchez G, Garcés-Alvarez ME, Aguirre-Cruz L, Velasco-Velázquez MA (2016) IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol 290:22–25

    CAS  PubMed  Google Scholar 

  37. Merskey HE (1986) Classification of chronic pain: Descriptions of chronic pain syndromés and definitions of pain terms. Pain 3:226

    Google Scholar 

  38. Mochizucki D (2004) Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol 19:S15–S19

    CAS  PubMed  Google Scholar 

  39. Moriguchi S, Yamada M, Takano H, Nagashima T, Takahata K, Yokokawa K, Ito T, Ishii T, Kimura Y, Zhang MR, Mimura M (2017) Norepinephrine transporter in major depressive disorder: a PET study. Am J Psychiatry 174:36–41

    PubMed  Google Scholar 

  40. Morris RG (1981) Spatial localization does not depend on the presence of local cues. Learn Motiv 12:239–260

    Google Scholar 

  41. Nagakura Y, Oe T, Aoki T, Matsuoka N (2009) Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia. Pain 146:26–33

    CAS  PubMed  Google Scholar 

  42. Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876

    CAS  PubMed  Google Scholar 

  43. Oliveira Miranda D, Soares de Lima TA, Ribeiro Azevedo L, Feres O, Ribeiro da Rocha JJ, Pereira-da-Silva G (2014) Pro-inflammatory cytokines correlate with depression and anxiety in colorectal cancer patients. BioMed Res Int. https://doi.org/10.1155/2014/739650

  44. Ozgocmen S, Ozyurt H, Sogut S, Akyol O (2006) Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide. Rheumatol Int 26:585–597

    CAS  PubMed  Google Scholar 

  45. Park BK, Kim YR, Kim YH, Yang C, Seo CS, Jung IC, Jang IS, Kim SH, Lee MY (2018). Antidepressant-like effects of gyejibokryeong-hwan in a mouse model of reserpine-induced depression. BioMed Res Int. https://doi.org/10.1155/2018/5845491

  46. Patel PR, Hegde ML, Theruvathu J, Mitra SA, Boldogh I, Sowers L (2015) Norepinephrine reduces reactive oxygen species (ROS) and DNA damage in ovarian surface epithelial cells. J Bioanal Biomed 7:75

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    CAS  PubMed  Google Scholar 

  48. Pujol J, López-Solà M, Ortiz H, Vilanova JC, Harrison BJ, Yücel M, Soriano-Mas C, Cardoner N, Deus J (2009) Mapping brain response to pain in fibromyalgia patients using temporal analysis of FMRI. PLoS One 4:e5224

    PubMed  PubMed Central  Google Scholar 

  49. Shu K, Kuang N, Zhang Z, Hu Z, Zhang Y, Fu Y, Min W (2014) Therapeutic effect of daphnetin on the autoimmune arthritis through demethylation of proapoptotic genes in synovial cells. J Transl Med 12:287

    PubMed  PubMed Central  Google Scholar 

  50. Singh L, Kaur A, Bhatti MS, Bhatti R (2019) Possible molecular mediators involved and mechanistic insight into fibromyalgia and associated co-morbidities. Neurochem Res 44:1517–1532

    CAS  PubMed  Google Scholar 

  51. Song B, Wang Z, Liu Y, Xu S, Huang G, Xiong Y, Zhang S, Xu L, Deng X, Guan S (2014) Immunosuppressive activity of daphnetin, one of coumarin derivatives, is mediated through suppression of NF-κB and NFAT signaling pathways in mouse T cells. PLoS One 9:e96502

    PubMed  PubMed Central  Google Scholar 

  52. Sousa FS, Birmann PT, Baldinotti R, Fronza MG, Balaguez R, Alves D, Brüning CA, Savegnago L (2018) α-(phenylselanyl) acetophenone mitigates reserpine-induced pain–depression dyad: behavioral, biochemical and molecular docking evidences. Brain Res Bull 142:129–137

    CAS  PubMed  Google Scholar 

  53. Staud R (2006) Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther 8:208

    PubMed  PubMed Central  Google Scholar 

  54. Subakanmani S, Murugan S, Devi PU (2016) Evaluation of antidepressant like effects of ethanolic Hypericum hookerianum and its glycosidic flavonoid enriched extract in reserpine induced swiss albino mice. Asian J Biochem 11:1–3

    CAS  Google Scholar 

  55. Taylor CP (2009) Mechanisms of analgesia by gabapentin and pregabalin–calcium channel α2-δ [Cavα2-δ] ligands. Pain 142:13–16

    CAS  PubMed  Google Scholar 

  56. Thompson T, Correll CU, Gallop K, Vancampfort D, Stubbs B (2016) Is pain perception altered in people with depression? A systematic review and meta-analysis of experimental pain research. J Pain 17:1257–1272

    PubMed  Google Scholar 

  57. Tong J, Meyer JH, Furukawa Y, Boileau I, Chang LJ, Wilson AA, Houle S (2013) Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies. J Cereb Blood Flow Metab 33:863–871

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Tort S, Urrútia G, Nishishinya MB, Walitt B (2012) Monoamine oxidase inhibitors 24 (MAOIs) for fibromyalgia syndrome. Cochrane Database Syst Rev CD009807.https://doi.org/10.1002/14651858.CD009807

  59. Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH (2001) Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology 40:743–749

    CAS  PubMed  Google Scholar 

  60. Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E, Muscoli C, Mollace V, Ndengele M, Ischiropoulos H, Salvemini D (2004) A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther 309:869–878

    CAS  PubMed  Google Scholar 

  61. Wang Z, Wang Q, Wang C, Xu X, Yu H (2017) Tetramethylpyrazine attenuates periorbital allodynia and neuroinflammation in a model of traumatic brain injury. J Inflamm 14:13

    Google Scholar 

  62. Wang G, Wang X, Xun Z, Sun Q, Xing B, Li ZD (2019) The prospect of daphnetin against drug-resistant bacteria: a mini review. J Microbiol Biotechn 8:34–35

    Google Scholar 

  63. Wood PB (2008) Role of central dopamine in pain and analgesia. Expert Rev Neurother 8:781–797

    CAS  PubMed  Google Scholar 

  64. Wood PB, Holman AJ, Jones KD (2007a) Novel pharmacotherapy for fibromyalgia. Expert Opin Investig Drugs 16:829–841

    CAS  PubMed  Google Scholar 

  65. Wood PB, Patterson JC II, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL (2007b) Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain 8:51–58

    CAS  PubMed  Google Scholar 

  66. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA (2007c) Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 25:3576–3582

    PubMed  Google Scholar 

  67. Xu Y, Wang C, Klabnik J, O’Donnell M (2014) Novel therapeutic targets in depression and anxiety: antioxidants as a candidate treatment. Curr Neuropharmacol 12:108–119

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang XG, Mou YH, Wang YJ, Wang J, Li YY, Kong RH, Ding M, Wang D, Guo C (2019) Design, synthesis, and evaluation of monoamine oxidase A inhibitors-indocyanine dyes conjugates as targeted antitumor agents. Molecules 24:1400

    CAS  PubMed Central  Google Scholar 

  69. Yao X, Li L, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL (2020) Attenuation of reserpine-induced fibromyalgia via ROS and serotonergic pathway modulation by fisetin, a plant flavonoid polyphenol. Exp Ther Med 19:1343–1355

    CAS  PubMed  Google Scholar 

  70. Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC (2013) IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 125:897–908

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Youdim MB, Riederer PF (2004) A review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson’s disease. Neurology 63:S32–S35

    PubMed  Google Scholar 

  72. Youdim MBH, Sandler M (1968) Activation of monoamine oxidase and inhibition of aldehyde dehydrogenase by reserpine. Eur J Pharmacol 4:105–108

    CAS  PubMed  Google Scholar 

  73. Zhang JM, An J (2007) Cytokines, inflammation and pain. Int Anesthesiol Clin 45:27–37

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang JM, Li H, Liu B, Brull SJ (2002) Acute topical application of tumor necrosis factor α evokes protein kinase A-dependent responses in rat sensory neurons. J Neurophysiol 88:1387–1392

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to the Department of Science and Technology, Government of India, for funding received under EMR (EMR/2016/005878). The authors gratefully acknowledge the financial support received from the University Grants Commission under RUSA 2.0 scheme.

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Department of Science and Technology, Government of India (EMR/2016/005878), and University Grants Commission, RUSA 2.0 scheme.

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Correspondence to Rajbir Bhatti.

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The whole investigation involving the use of mice was approved by the Institutional Animal Ethics Committee (Approval No. 226/CPCSEA/2018/23) and the experiments were performed according to ethical guidelines of the Ministry of Environment and Forests, Government of India.

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Singh, L., Kaur, A., Singh, A.P. et al. Daphnetin, a natural coumarin averts reserpine-induced fibromyalgia in mice: modulation of MAO-A. Exp Brain Res 239, 1451–1463 (2021). https://doi.org/10.1007/s00221-021-06064-1

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Keywords

  • Daphnetin
  • Fibromyalgia
  • MAO-A
  • Neurotransmitters
  • Cytokines
  • Oxidative stress