Abstract
The effects of Piper malacophyllum (C. Pesl) C. DC extracts and its isolated compounds were analysed in a mouse model of primary dysmenorrhoea (PD). Female Swiss mice (6–8 weeks old) on proestrus were intraperitoneally treated with estradiol benzoate for 3 days, to induce PD. Twenty-four hours later, animals were treated 24 h later with vehicle, plant extract, gibbilimbol B, 4,6-dimethoxy-5-E-phenylbutenolide, mixture of 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, or ibuprofen. One hour later, oxytocin was injected and the numbers of abdominal writhing were counted. Then, mice were euthanized and uteri were collected for morphometrical and histological analyses. The effects of P. malacophyllum in inflammation were investigated in mouse peritoneal neutrophils culture stimulated with LPS or fMLP (chemotaxis and mediator release). Finally, uterus contractile and relaxing responses were assessed. Similar to ibuprofen, P. malacophyllum extract and isolated compounds reduced abdominal writhing in mice with PD. Histology indicated a marked neutrophil and mast cell infiltrate in the uterus of PD animals which was attenuated by the extract. The compounds and the extract reduced neutrophil chemotaxis and inflammatory mediator release by these cells. Reduced TNF levels were also observed in uteri of PD mice treated with P. malacophyllum. The extract did not affect spontaneous uterine contractions nor those induced by carbachol or KCl. However, it caused relaxation of oxytocin-induced uterine contraction, an effect blunted by H1 receptor antagonist. Overall the results indicate that P. malacophyllum may represent interesting natural tools for reliving PD symptoms, reducing the triad of pain, inflammation and spasmodic uterus behaviour.
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References
Agostinis C, Mangogna A, Bossi F et al (2019) Uterine immunity and microbiota: a shifting paradigm. Front Immunol 10:2387. https://doi.org/10.3389/fimmu.2019.02387
Anaf V, Chapron C, El Nakadi I et al (2006) Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 86:1336–1343. https://doi.org/10.1016/J.FERTNSTERT.2006.03.057
Arrowsmith S, Wray S (2014) Oxytocin: its mechanism of action and receptor signalling in the myometrium. J Neuroendocrinol 26:356–369. https://doi.org/10.1111/JNE.12154
Assefa N, Demissie A, Hailemeskel S (2016) Primary dysmenorrhea magnitude, associated risk factors, and its effect on academic performance: evidence from female university students in Ethiopia. Int J Womens Health 8:489–496. https://doi.org/10.2147/IJWH.S112768
Benvenutti L, Nunes R, Venturi I et al (2021) Anti-inflammatory and healing activity of the hydroalcoholic fruit extract of Solanum diploconos (Mart.) Bohs. J Immunol Res 2021:1–13. https://doi.org/10.1155/2021/9957451
Bódis J, Tinneberg HR, Schwarz H et al (2009) The effect of histamine on progesterone and estradiol secretion of human granulosa cells in serum-free culture. Gynecol Endocrinol 7:235–239. https://doi.org/10.3109/09513599309152507
Broering MF, Nunes R, De Faveri R et al (2019) Effects of Tithonia diversifolia (Asteraceae) extract on innate inflammatory responses. J Ethnopharmacol 242:112041. https://doi.org/10.1016/j.jep.2019.112041
Carnaúba PU, Mengarda AC, Rodrigues VC, Morais TR, Oliveira A, Lago JHG, Moraes J (2021) Evaluation of gibbilimbol B, isolated from Piper malacophyllum (Piperaceae), as an antischistosomal agent. Chem Biodivers 18:10. https://doi.org/10.1002/cbdv.202100503
Chantler I, Mitchell D, Fuller A (2009) Diclofenac potassium attenuates dysmenorrhea and restores exercise performance in women with primary dysmenorrhea. J Pain 10:191–200. https://doi.org/10.1016/J.JPAIN.2008.08.006
Chen HY, Lin YH, Su IH et al (2014) Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med 22:116–125. https://doi.org/10.1016/J.CTIM.2013.11.012
Ciebiera M, Włodarczyk M, Zgliczyńska M et al (2018) The role of tumor necrosis factor α in the biology of uterine fibroids and the related symptoms. Int J Mol Sci 19:3869. https://doi.org/10.3390/IJMS19123869
Coe FG, Anderson GJ (1996) Screening of medicinal plants used by the Garífuna of eastern Nicaragua for bioactive compounds. J Ethnopharmacol 53:29–50. https://doi.org/10.1016/0378-8741(96)01424-9
da Jesuíno FW, R, Reis JP, Whitaker JCP, et al (2019) Effect of Synadenium grantii and its isolated compound on dysmenorrhea behavior model in mice. Inflammopharmacology 27:613–620. https://doi.org/10.1007/S10787-018-0501-1
Dawood MY, Khan-Dawood FS (2007) Clinical efficacy and differential inhibition of menstrual fluid prostaglandin F2α in a randomized, double-blind, crossover treatment with placebo, acetaminophen, and ibuprofen in primary dysmenorrhea. Am J Obstet Gynecol 196:35.e1-35.e5. https://doi.org/10.1016/J.AJOG.2006.06.091
de Oliveira A, Silva CA, Silva AM et al (2010) Development and validation of a micellar electrokinetic chromatography method for quantitative determination of butenolides in Piper malacophyllum (C. Presl) C. DC Phytochem Anal 21:428–433. https://doi.org/10.1002/PCA.1213
de Oliveira A, Mesquita JT, Tempone AG et al (2012) Leishmanicidal activity of an alkenylphenol from Piper malacophyllum is related to plasma membrane disruption. Exp Parasitol 132:383–387. https://doi.org/10.1016/J.EXPPARA.2012.08.019
Durant-Archibold AA, Santana AI, Gupta MP (2018) Ethnomedical uses and pharmacological activities of most prevalent species of genus Piper in Panama: a review. J Ethnopharmacol 217:63–82
Fang L, Gu C, Liu X et al (2017) Metabolomics study on primary dysmenorrhea patients during the luteal regression stage based on ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Mol Med Rep 15:1043–1050. https://doi.org/10.3892/MMR.2017.6116
Feng C, Beller EM, Bagga S, Boyce JA (2006) Human mast cells express multiple EP receptors for prostaglandin E2 that differentially modulate activation responses. Blood 107:3243–3250. https://doi.org/10.1182/blood-2005-07-2772
Ferreira PK, Campos MM, Calixto JB (2000) The role of sensorial neuropeptides in the edematogenic responses mediated by B(1) agonist des-Arg(9)-BK in rats pre-treated with LPS. Regul Pept 89(1–3):29–35. https://doi.org/10.1016/s0167-0115(00)00094-x
Gao L, Xiao Z, Jia C, Wang W (2019) A comparison of the efficacy of Chinese herbal medicines in the treatment of primary dysmenorrhea: A network meta-analysis protocol. Medicine (Baltimore). https://doi.org/10.1097/MD.0000000000015100
Girón LM, Freire V, Alonzo A, Cáceres A (1991) Ethnobotanical survey of the medicinal flora used by the Caribs of Guatemala. J Ethnopharmacol 34:173–187. https://doi.org/10.1016/0378-8741(91)90035-C
Giustarini D, Rossi R, Milzani A, Dalle-Donne I (2008) Nitrite and nitrate measurement by griess reagent in human plasma: evaluation of interferences and standardization. Methods Enzymol 440:361–380
Grulović B, Ribič Pucelj M, Krnić M, Kokić V (2013) Impact of prostaglandin F2-alpha and tumor necrosis factor-alpha (TNF-a) on Pain in patients undergoing thermal balloon endometrial ablation. Coll Antropol 37:1185–1190
Guimarães I, Póvoa AM (2020) Primary dysmenorrhea: assessment and treatment. Rev Bras Ginecol Obstet 42:501–507. https://doi.org/10.1055/S-0040-1712131
Gul E, Kavak EC (2018) Eotaxin levels in patients with primary dysmenorrhea. J Pain Res 11:611–613. https://doi.org/10.2147/JPR.S146603
Harada T (2013) Dysmenorrhea and endometriosis in young women. Yonago Acta Med 56:81
Horowitz A, Menice CB, Laporte KG (1996) Mechanisms of smooth muscle contraction. Phys Rev 76:967–1003
Iacovides S, Avidon I, Baker FC (2015) What we know about primary dysmenorrhea today: a critical review. Hum Reprod Update 21:762–778. https://doi.org/10.1093/HUMUPD/DMV039
Il Kim, Nam HJ, Kim M et al (2017) Effects of herbal medicine for dysmenorrhea treatment on accompanied acne vulgaris: a study protocol for a randomized controlled trial. BMC Complement Altern Med. https://doi.org/10.1186/S12906-017-1813-1
Jahangirifar M, Taebi M, Dolatian M (2018) The effect of cinnamon on primary dysmenorrhea: a randomized, double-blind clinical trial. Complement Ther Clin Pract 33:56–60. https://doi.org/10.1016/j.ctcp.2018.08.001
Kaplan Ö, Naziroǧlu M, Güney M, Aykur M (2013) Non-steroidal anti-inflammatory drug modulates oxidative stress and calcium ion levels in the neutrophils of patients with primary dysmenorrhea. J Reprod Immunol 100:87–92. https://doi.org/10.1016/J.JRI.2013.10.004
Lago JHG, Tanizaki TM, Young MCM et al (2005) Antifungal piperolides from Piper malacophyllum (Prels) C. DC J Braz Chem Soc 16:153–156. https://doi.org/10.1590/S0103-50532005000200005
Lee SK, Kim CJ, Kim D-J, Kang J (2015) Immune cells in the female reproductive tract. Immune Netw 15:16. https://doi.org/10.4110/IN.2015.15.1.16
Leem J, Jo J, Kwon C-Y et al (2019) Herbal medicine (Hyeolbuchukeo-tang or Xuefu Zhuyu decoction) for treating primary dysmenorrhea. Medicine (Baltimore) 98:e14170. https://doi.org/10.1097/MD.0000000000014170
Leimert KB, Verstraeten BSE, Messer A et al (2019) Cooperative effects of sequential PGF2α and IL-1β on IL-6 and COX-2 expression in human myometrial cells. Biol Reprod 100:1370. https://doi.org/10.1093/BIOLRE/IOZ029
Li R, Yang J, Shi Y et al (2014) Chemical composition, antimicrobial and anti-inflammatory activities of the essential oil from Maqian (Zanthoxylum myriacanthum var. pubescens) in Xishuangbanna, SW China. J Ethnopharmacol 158(Pt A):43–8. https://doi.org/10.1016/j.jep.2014.10.006
Lima CNF, de Lima LF, Correia DB et al (2020) Systematic review: medicinal use and scientific elucidation of the Piper genus for the treatment of symptoms and inflammatory diseases. J Med Plants Res 14:62–72. https://doi.org/10.5897/JMPR2019.6855
Liu P, Duan JA, Hua YQ et al (2011) Effects of Xiang-Fu-Si-Wu decoction and its main components for dysmenorrhea on uterus contraction. J Ethnopharmacol 133:591–597. https://doi.org/10.1016/J.JEP.2010.10.042
Marcondes FK, Bianchi FJ, Tanno AP (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62:609–614. https://doi.org/10.1590/S1519-69842002000400008
Martínez-Mir MI, Estañ L, Morales-Olivas FJ, Rubio E (1992) Effect of histamine and histamine analogues on human isolated myometrial strips. Br J Pharmacol 107:528–531. https://doi.org/10.1111/J.1476-5381.1992.TB12778.X
Martínez-Mir I, Herrero J, Estañ L et al (1993) Effect of histamine on the longitudinal and circular muscle of the oestrogen dominated rat uterus. Agents Actions 39(1–2):1–5
Menzies FM, Higgins CA, Shepherd MC et al (2012) Mast cells reside in myometrium and cervix, but are dispensable in mice for successful pregnancy and labor. Immunol Cell Biol 90:321–329. https://doi.org/10.1038/ICB.2011.40
Menzies-Gow A, Ying S, Phipps S, Kay AB (2004) Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans. Clin Exp Allergy 34:1276–1282. https://doi.org/10.1111/J.1365-2222.2004.02014.X
Mesquita JMO, Cavaleiro C, Cunha AP et al (2005) Estudo comparativo dos óleos voláteis de algumas espécies de Piperaceae. Rev Bras Farmacogn 15:6–12. https://doi.org/10.1590/S0102-695X2005000100003
Michel J, Duarte RE, Bolton JL et al (2007) Medical potential of plants used by the Q’eqchi Maya of Livingston, Guatemala for the treatment of women’s health complaints. J Ethnopharmacol 114:92–101. https://doi.org/10.1016/J.JEP.2007.07.033
Michel JL, Chen Y, Zhang H et al (2010) Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae). J Ethnopharmacol 129:220. https://doi.org/10.1016/J.JEP.2010.03.008
Michel JL, Caceres A, Mahady GB (2016) Ethnomedical research and review of Q’eqchi Maya women’s reproductive health in the Lake Izabal region of Guatemala: Past, present and future prospects. J Ethnopharmacol 178:307–322. https://doi.org/10.1016/J.JEP.2015.12.006
Mobarakeh JI, Sakurada S, Katsuyama S et al (2000) Role of histamine H(1) receptor in pain perception: a study of the receptor gene knockout mice. Eur J Pharmacol 391:81–89. https://doi.org/10.1016/S0014-2999(00)00060-1
Nakae S, Suto H, Kakurai M et al (2005) Mast cells enhance T cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci U S A 102:6467–6472
Nelson RD, Quie PG, Simmons RL (1975) Chemotaxis under agarose: a new and simple method for measuring chemotaxis and spontaneous migration of human polymorphonuclear leukocytes and monocytes. J Immunol 115:1650–1656
Orjala J, Mian P, Rali T, Sticher O (1998) Gibbilimbols A−D, cytotoxic and antibacterial alkenylphenols from Piper gibbilimbum. J Nat Prod 61:939–941. https://doi.org/10.1021/NP970529I
Ortiz MI, Murguía-Cánovas G, Vargas-López LC et al (2016) Naproxen, paracetamol and pamabrom versus paracetamol, pyrilamine and pamabrom in primary dysmenorrhea: a randomized, double-blind clinical trial. Medwave 16:e6587. https://doi.org/10.5867/MEDWAVE.2016.09.6587
Paszcuk AF, Quintão NL, Fernandes ES et al (2008) Mechanisms underlying the nociceptive and inflammatory responses induced by trypsin in the mouse paw. Eur J Pharmacol 581(1–2):204–215. https://doi.org/10.1016/j.ejphar.2007.11.025
Perez MC, Furth EE, Matzumura PD, Lyttle CR (1996) Role of eosinophils in uterine responses to estrogen. Biol Reprod 54:249–254. https://doi.org/10.1095/BIOLREPROD54.1.249
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. https://doi.org/10.1016/S0014-2999(03)01272-X
Pu B-C, Fang L, Gao L-N et al (2015) Animal study on primary dysmenorrhoea treatment at different administration times. Evidence-Based Complement Altern Med 2015:1–8. https://doi.org/10.1155/2015/367379
Rudick CN, Bryce PJ, Guichelaar LA et al (2008) (2008) Mast cell-derived histamine mediates cystitis pain. PLoS ONE 3:e2096
Salehi B, Zakaria ZA, Gyawali R et al (2019) Piper species: a comprehensive review on their phytochemistry, biological activities and applications. Molecules. https://doi.org/10.3390/MOLECULES24071364
Santos TG, Rebelo RA, Dalmarco EM et al (2012) Chemical composition and antimicrobial activity of leaf essential oil from Piper malacophyllum (C. Presl.) C. DC Quim Nova 35:477–481. https://doi.org/10.1590/S0100-40422012000300007
Sharghi M, Mansurkhani SM, Ashtary-Larky D et al (2019) An update and systematic review on the treatment of primary dysmenorrhea. JBRA Assist Reprod 23:51–57. https://doi.org/10.5935/1518-0557.20180083
Stevanatto G, Gomes PB (2013) Western Blot. In: Siviero F (ed) Bases moleculares e metodologia de pesquisa. São Paulo, Roca Ltd, pp 250–266
Sun L, Liu L, Zong S et al (2016) Traditional Chinese medicine Guizhi Fuling capsule used for therapy of dysmenorrhea via attenuating uterus contraction. J Ethnopharmacol 191:273–279. https://doi.org/10.1016/j.jep.2016.06.042
Sun L, Liu LN, Li JC et al (2017) The essential oil from the twigs of Cinnamomum cassia Presl inhibits oxytocin-induced uterine contraction in vitro and in vivo. J Ethnopharmacol 206:107–114. https://doi.org/10.1016/j.jep.2017.05.023
Tavonic A, Jimenez M, Fernandez E (2000) Lack of effect of nitric oxide on KCl-, acetylcholine-and substance P-induced contractions in ileal longitudinal muscle of the rat. Life Sci 67:531–541
Theoharides TC, Stewart JM (2015) Genitourinary mast cells and survival. Transl Androl Urol 4:579–586. https://doi.org/10.3978/J.ISSN.2223-4683.2015.10.04
Varela MT, Lima ML, Galuppo MK et al (2017) New alkenyl derivative from Piper malacophyllum and analogues: Antiparasitic activity against Trypanosoma cruzi and Leishmania infantum. Chem Biol Drug Des 90:1007–1011. https://doi.org/10.1111/CBDD.12986
Vrachnis N, Malamas FM, Sifakis S et al (2011) The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents. Int J Endocrinol 2011:350546. https://doi.org/10.1155/2011/350546
Wei Y, Ma T, Wang H et al (2018) Extracts of compound Muniziqi granule suppressed uterus contraction and ameliorated oxytocin-induced primary dysmenorrhea. J Ethnopharmacol 223:33–40. https://doi.org/10.1016/j.jep.2018.05.024
Willets JM, Taylor AH, Shaw H et al (2008) Selective regulation of H1 histamine receptor signaling by G protein-coupled receptor kinase 2 in uterine smooth muscle cells. Mol Endocrinol 22:1893–1907. https://doi.org/10.1210/ME.2007-0463
Xia MY, Yang J, Zhang PH et al (2018) Amides, isoquinoline alkaloids and dipeptides from the aerial parts of piper mullesua. Nat Products Bioprospect 8:419. https://doi.org/10.1007/S13659-018-0180-Z
Yacubovich Y, Cohen N, Tene L, Kalichman L (2019) The prevalence of primary dysmenorrhea among students and its association with musculoskeletal and myofascial pain. J Bodyw Mov Ther 23:785–791. https://doi.org/10.1016/J.JBMT.2019.05.006
Yang L, Cao Z, Yu B, Chai C (2015) An in vivo mouse model of primarydysmenorrhea. Exp Anim 64:295. https://doi.org/10.1538/EXPANIM.14-0111
Acknowledgements
This work was supported by grants and financial support from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Fundação de Apoio a Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC), MCTI/CNPQ/CAPES/FAPS Nº 16/2014 – INCT INOVAMED; (process # 465430/2014-7) Brasil. The co-authors were supported by grants, as following: J.P.R. and M.C.C (Programa de Bolsas Universitárias de Santa Catarina – UNIEDU Bolsa do Art. 170 da Constituição Estadual), L.B., R.N., C.R.V. (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES), J.M. and F.C.G. (Programa FAPESC/CAPES de Recursos Humanos em CTI), N.L.M.Q. (CNPq – 305550/2018-7), J.R.S. (CNPq—process # 429505/2018-3; 310326/2020-6). R.C.V.S. is grateful for the Post-Doctoral scholarship and financial support from PNPD/CAPES.
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JRS, NLMQ and PS conceived and designed research. JPV, LB, RN, FCG, MSC, RCVS, JM, CRV, JCPW, FWRJ and MCC conducted experiments. AM and CMS contributed with analytical tools. JRS, NLMQ, MVDP, PS and AM analysed data. JRS, NLMQ, AM, CMS and PS drafted, critically revised and wrote the final manuscript. All authors read and approved the manuscript.
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Quintão, N.L.M., Reis, J.P., Benvenutti, L. et al. Involvement of a neutrophil-mast cell axis in the effects of Piper malacophyllum (C. PESL) C. DC extract and its isolated compounds in a mouse model of dysmenorrhoea. Inflammopharmacol 30, 2489–2504 (2022). https://doi.org/10.1007/s10787-022-01032-9
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DOI: https://doi.org/10.1007/s10787-022-01032-9