Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Rosmarinic acid reverses the effects of metronidazole-induced infertility in male albino rats

Zina M. Al-Alami A D , Ziad A. Shraideh B and Mutasem O. Taha C
+ Author Affiliations
- Author Affiliations

A Faculty of Pharmacy, Isra University, PO Box 22, Amman 11622, Jordan.

B Department of Biological Sciences, Faculty of Science, The University of Jordan, Amman 11942, Jordan.

C Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.

D Corresponding author. Email: zina.alalami@iu.edu.jo

Reproduction, Fertility and Development - https://doi.org/10.1071/RD16174
Submitted: 7 November 2015  Accepted: 22 October 2016   Published online: 23 November 2016

Abstract

Rosmarinic acid (RA) is a natural antioxidant that has many biological activities. In the present study we investigated the potential of RA to reverse the negative effects of the widely used antibiotic and antiprotozoal agent metronidazole (MTZ), which is known to induce reversible male infertility. Two doses of RA (5 and 15 mg kg–1) were studied in sexually mature rats with and without MTZ-induced infertility. Rats were intraperitoneally injected with 5 mg kg–1 RA or 15 mg kg–1 RA (in distilled water) and, 45 min later, they were intraperitoneally injected with 40 mg kg–1 MTZ (in distilled water). Cauda epididymidal sperm suspensions were used to assess sperm count, motility and morphology. Histological and ultrastructural studies were performed on the testes and cauda epididymidis. In rats in which infertility was not induced, neither dose of RA affected the parameters assessed. However, in sexually mature rats in which infertility was induced by 40 mg kg–1 MTZ, RA at both 5 and 15 mg kg–1 ameliorated the damaging effects of MTZ on final bodyweight (30 days later), sperm motility and morphology. Only 5 mg kg–1 RA, and not 15 mg kg–1 RA, improved the harmful effects of MTZ on the sperm count and testis ultrastructure. The findings of the present study have considerable clinical implications and suggest a possible use for RA to reverse the negative effects of MTZ on male fertility, the male reproductive system and spermatogenesis.

Additional keywords: antioxidant, nutraceutical, spermatogenesis.


References

Abdallah, F. B., Fetou, H., Zribi, N., Fakhfakh, F., and Keskes, L. (2012). Protective role of caffeic acid on lambda cyhalothrin-induced changes in sperm characteristics and testicular oxidative damage in rats. Toxicol. Ind. Health 28, 639–647.
Protective role of caffeic acid on lambda cyhalothrin-induced changes in sperm characteristics and testicular oxidative damage in rats.CrossRef | open url image1

Al-Alami, Z. M., Shraideh, Z. A., and Taha, M. O. (2015). β-Caryophyllene as putative male contraceptive: enhances spermatogenesis but not spermiogenesis in albino rats. Med. Chem. Res. 24, 3876–3884.
β-Caryophyllene as putative male contraceptive: enhances spermatogenesis but not spermiogenesis in albino rats.CrossRef | 1:CAS:528:DC%2BC2MXhtlyjtbzL&md5=e80870be02c81080735a29355e852164CAS | open url image1

Creasy, D. M. (2003). Evaluation of testicular toxicology: a synopsis and discussion of the recommendations proposed by the Society of Toxicologic Pathology. Birth Defects Res. B Dev. Reprod. Toxicol. 68, 408–415.
Evaluation of testicular toxicology: a synopsis and discussion of the recommendations proposed by the Society of Toxicologic Pathology.CrossRef | 1:CAS:528:DC%2BD3sXptFOjtro%3D&md5=15384d392c81c1db3a315780435d4c78CAS | open url image1

De Oliveira, N. C., Sarmento, M. S., Nunes, E. A., Porto, C. M., Rosa, D. P., Bona, S. R., Rodrigues, G., Marroni, N. P., Pereira, P., and Picada, J. N. (2012). Rosmarinic acid as a protective agent against genotoxicity of ethanol in mice. Food Chem. Toxicol. 50, 1208–1214.
Rosmarinic acid as a protective agent against genotoxicity of ethanol in mice.CrossRef | 1:CAS:528:DC%2BC38XmtVeqsrs%3D&md5=88458a2b7e33af3545b0cdb03f4f771bCAS | open url image1

del Baño, M. J., Lorente, J., Castillo, J., Benavente-Garcia, O., del Río, J. A., Ortuño, A., Quirin, K. W., and Gerard, D. (2003). Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity. J. Agric. Food Chem. 51, 4247–4253.
Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity.CrossRef | open url image1

Dias, T. R., Alves, M. G., Bernardino, R. L., Martins, A. D., Moreira, A. C., Silva, J., Barros, A., Sousa, M., Silva, B. M., and Oliveira, P. F. (2015). Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: relevance for male fertility. Toxicology 328, 12–20.
Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: relevance for male fertility.CrossRef | 1:CAS:528:DC%2BC2cXitV2nur%2FI&md5=e3505ac39056cd40e233480a19d72599CAS | open url image1

Dutertre, M., and Smith, C. L. (2000). Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J. Pharmacol. Exp. Ther. 295, 431–437.
| 1:CAS:528:DC%2BD3cXnsl2ks7c%3D&md5=56313fc8493c0581a9763d576d918257CAS | open url image1

Fadel, O., El Kirat, K., and Morandat, S. (2011). The natural antioxidant rosmarinic acid spontaneously penetrates membranes to inhibit lipid peroxidation in situ. Biochim. Biophys. Acta 1808, 2973–2980.
The natural antioxidant rosmarinic acid spontaneously penetrates membranes to inhibit lipid peroxidation in situ.CrossRef | 1:CAS:528:DC%2BC3MXhtlejt7rM&md5=498535985bd8cc1f9355add2c7c87805CAS | open url image1

Farmakiotis, D., Farmakis, C., Rousso, D., Kourtis, A., Katsikis, I., and Panidis, D. (2007). The beneficial effects of toremifene administration on the hypothalamic–pituitary–testicular axis and sperm parameters in men with idiopathic oligozoospermia. Fertil. Steril. 88, 847–853.
The beneficial effects of toremifene administration on the hypothalamic–pituitary–testicular axis and sperm parameters in men with idiopathic oligozoospermia.CrossRef | 1:CAS:528:DC%2BD2sXhtlSltL3L&md5=f044f0593fd31e371471a2abf7414ad2CAS | open url image1

Ghaffari, H., Venkataramana, M., Jalali Ghassam, B., Chandra Nayaka, S., Nataraju, A., Geetha, N. P., and Prakash, H. S. (2014). Rosmarinic acid mediated neuroprotective effects against H2O2-induced neuronal cell damage in N2A cells. Life Sci. 113, 7–13.
Rosmarinic acid mediated neuroprotective effects against H2O2-induced neuronal cell damage in N2A cells.CrossRef | 1:CAS:528:DC%2BC2cXhsVOhs7vN&md5=88b64c05dc262f4c7857193778e24429CAS | open url image1

Ghosh, E., Ghosh, A., Ghosh, A. N., Nozaki, T., and Ganguly, S. (2009). Oxidative stress-induced cell cycle blockage and a protease-independent programmed cell death in microaerophilic Giardia lamblia. Drug Des. Devel. Ther. 3, 103–110.
| 1:CAS:528:DC%2BD1MXoslSmsL4%3D&md5=523b44dc345b251636dc8bdf0d706333CAS | open url image1

Huang, Y. S., and Zhang, J. T. (1992). [Antioxidative effect of three water-soluble components isolated from Salvia miltiorrhiza in vitro.] Yao Xue Xue Bao 27, 96–100.
| 1:CAS:528:DyaK38Xit1yhsrY%3D&md5=b8551d9e186505c83cbca698b409557dCAS | open url image1

Jones, R. (1998). Plasma membrane structure and remodelling during sperm maturation in the epididymis. J. Reprod. Fertil. Suppl. 53, 73–84.
| 1:CAS:528:DyaK1MXitVekuro%3D&md5=08dd02e795f6f7c016b02596fdbac1faCAS | open url image1

Jung, B. I., Kim, M. S., Kim, H., Kim, D., Yang, J., Her, S., and Song, Y. S. (2010). Caffeic acid phenethyl ester, a component of beehive propolis, is a novel selective estrogen receptor modulator. Phytother. Res. 24, 295–300.
| 1:CAS:528:DC%2BC3cXivValur8%3D&md5=d9e787d0bad5046ae49ac4dc39752ad3CAS | open url image1

Khaki, A., Imani, S., and Golzar, F. (2012). Effects of rosmarinic acid on male sex hormones (testosterone–FSH–LH) and testis tissue apoptosis after exposure to electromagnetic field (EMF) in rats. Afr. J. Pharm. Pharmacol. 6, 248–252.
Effects of rosmarinic acid on male sex hormones (testosterone–FSH–LH) and testis tissue apoptosis after exposure to electromagnetic field (EMF) in rats.CrossRef | 1:CAS:528:DC%2BC38XivFaqur8%3D&md5=8d7b56d1c40e5feb3924e7a3948ab334CAS | open url image1

Lee, J., Jung, E., Kim, Y., Lee, J., Park, J., Hong, S., Hyun, C. G., Park, D., and Kim, Y. S. (2006). Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3. Br. J. Pharmacol. 148, 366–375.
Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3.CrossRef | 1:CAS:528:DC%2BD28XltVCjtrs%3D&md5=76f3d659a971e701d1fc798abaa0bdf4CAS | open url image1

Löfmark, S., Edlund, C., and Nord, C. E. (2010). Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin. Infect. Dis. 50, S16–S23.
Metronidazole is still the drug of choice for treatment of anaerobic infections.CrossRef | open url image1

Lucio, R. A., Tlachi-Lopez, J. L., Eguibar, J. R., and Agmo, A. (2013). Sperm count and sperm motility decrease in old rats. Physiol. Behav. 110–111, 73–79.
Sperm count and sperm motility decrease in old rats.CrossRef | open url image1

McClain, R. M., Downing, J. C., and Edgcomb, J. E. (1989). Effect of metronidazole on fertility and testicular function in male rats. Fundam. Appl. Toxicol. 12, 386–396.
Effect of metronidazole on fertility and testicular function in male rats.CrossRef | 1:CAS:528:DyaL1MXitVGit7o%3D&md5=5ab4b600e6cd6cecf338d03aa9ab70f0CAS | open url image1

Moss, J. L., Crosnoe, L. E., and Kim, E. D. (2013). Effect of rejuvenation hormones on spermatogenesis. Fertil. Steril. 99, 1814–1820.
Effect of rejuvenation hormones on spermatogenesis.CrossRef | 1:CAS:528:DC%2BC3sXnvVOht78%3D&md5=ef199929ce2afe62e4bb8326ac6d4146CAS | open url image1

Mudry, M. D., Palermo, A. M., Merani, M. S., and Carballo, M. A. (2007). Metronidazole-induced alterations in murine spermatozoa morphology. Reprod. Toxicol. 23, 246–252.
Metronidazole-induced alterations in murine spermatozoa morphology.CrossRef | 1:CAS:528:DC%2BD2sXhs1Smurw%3D&md5=d304602ce6f5822b03feb62485dcf0bbCAS | open url image1

Nakazawa, T., and Ohsawa, K. (1998). Metabolism of rosmarinic acid in rats. J. Nat. Prod. 61, 993–996.
Metabolism of rosmarinic acid in rats.CrossRef | 1:CAS:528:DyaK1cXlsFSksrg%3D&md5=1298abf0a2108a38da27a34a7dcd7086CAS | open url image1

Narayana, K., Prashanthi, N., Nayanatara, A., Kumar, H. H., Abhilash, K., and Bairy, K. L. (2005). Effects of methyl parathion (o,o-dimethyl o-4-nitrophenyl phosphorothioate) on rat sperm morphology and sperm count, but not fertility, are associated with decreased ascorbic acid level in the testis. Mutat. Res. 588, 28–34.
Effects of methyl parathion (o,o-dimethyl o-4-nitrophenyl phosphorothioate) on rat sperm morphology and sperm count, but not fertility, are associated with decreased ascorbic acid level in the testis.CrossRef | 1:CAS:528:DC%2BD2MXht1arsLzI&md5=089c9468b9f790c9bdd45736040babbdCAS | open url image1

Narayana, K., Verghese, S., and Jacob, S. S. (2009). l-Ascorbic acid partially protects two cycles of cisplatin chemotherapy-induced testis damage and oligo-astheno-teratospermia in a mouse model. Exp. Toxicol. Pathol. 61, 553–563.
l-Ascorbic acid partially protects two cycles of cisplatin chemotherapy-induced testis damage and oligo-astheno-teratospermia in a mouse model.CrossRef | 1:CAS:528:DC%2BC3cXkt1yltA%3D%3D&md5=e886711d0c5edc2888089787d5b9107cCAS | open url image1

Noorafshan, A., Karbalay-Doust, S., Valizadeh, A., Aliabadi, E., and Mirkhani, H. (2010). Ameliorative effects of curcumin on the seminiferous epithelium in metronidazole-treated mice: a stereological study. Toxicol. Pathol. 38, 366–371.
Ameliorative effects of curcumin on the seminiferous epithelium in metronidazole-treated mice: a stereological study.CrossRef | 1:CAS:528:DC%2BC3cXms1OntLc%3D&md5=bc01a97d0a0ce7484b79393de3a0d9f4CAS | open url image1

Noorafshan, A., Karbalay-Doust, S., Valizadeh, A., and Aliabadi, E. (2011). Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach. Exp. Toxicol. Pathol. 63, 627–633.
Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach.CrossRef | 1:CAS:528:DC%2BC3MXht1egu7vF&md5=2aa92e6312ba71e46d6722be0b98ddfbCAS | open url image1

Ohta, R., Takagi, A., Ohmukai, H., Marumo, H., Ono, A., Matsushima, Y., Inoue, T., Ono, H., and Kanno, J. (2012). Ovariectomized mouse uterotrophic assay of 36 chemicals. J. Toxicol. Sci. 37, 879–889.
Ovariectomized mouse uterotrophic assay of 36 chemicals.CrossRef | 1:CAS:528:DC%2BC38XhslSntrrE&md5=07217a856260bf83213f373384e257bdCAS | open url image1

Oliveira, P. F., Tomás, G. D., Dias, T. R., Martins, A. D., Rato, L., Alves, M. G., and Silva, B. M. (2015). White tea consumption restores sperm quality in prediabetic rats preventing testicular oxidative damage. Reprod. Biomed. Online 31, 544–556.
White tea consumption restores sperm quality in prediabetic rats preventing testicular oxidative damage.CrossRef | 1:CAS:528:DC%2BC2MXhtF2rsrzJ&md5=c78f7974df4d52a9fbcce556cd9b8b04CAS | open url image1

Oteiza, P. I., Erlejman, A. G., Verstraeten, S. V., Keen, C. L., and Fraga, C. G. (2005). Flavonoid-membrane interactions: a protective role of flavonoids at the membrane surface? Clin. Dev. Immunol. 12, 19–25.
Flavonoid-membrane interactions: a protective role of flavonoids at the membrane surface?CrossRef | 1:CAS:528:DC%2BD2MXhvFynu74%3D&md5=3f50689ef6152b3bfa31e273fe88fbc9CAS | open url image1

Petersen, M., and Simmonds, M. S. (2003). Rosmarinic acid. Phytochemistry 62, 121–125.
Rosmarinic acid.CrossRef | 1:CAS:528:DC%2BD38XptlCktLo%3D&md5=505ed72482357e8c181032ce98e6b5deCAS | open url image1

Seed, J., Chapin, R. E., Clegg, E. D., Dostal, L. A., Foote, R. H., Hurtt, M. E., Klinefelter, G. R., Makris, S. L., Perreault, S. D., Schrader, S., Seyler, D., Sprando, R., Treinen, K. A., Veeramachaneni, D. N., and Wise, L. D. (1996). Methods for assessing sperm motility, morphology, and counts in the rat, rabbit, and dog: a consensus report. ILSI Risk Science Institute Expert Working Group on Sperm Evaluation. Reprod. Toxicol. 10, 237–244.
Methods for assessing sperm motility, morphology, and counts in the rat, rabbit, and dog: a consensus report. ILSI Risk Science Institute Expert Working Group on Sperm Evaluation.CrossRef | 1:CAS:528:DyaK28XjslSqtL0%3D&md5=a5af1f32dae2bea6ee76ecb6b51ed214CAS | open url image1

Singh, S., Das Roy, L., and Giri, S. (2013). Curcumin protects metronidazole and X-ray induced cytotoxicity and oxidative stress in male germ cells in mice. Prague Med. Rep. 114, 92–102.
Curcumin protects metronidazole and X-ray induced cytotoxicity and oxidative stress in male germ cells in mice.CrossRef | 1:CAS:528:DC%2BC3sXhtlSqu77M&md5=2c6e31ed50ba5b6895fe74de4b610a22CAS | open url image1

Swarup, V., Ghosh, J., Ghosh, S., Saxena, A., and Basu, A. (2007). Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob. Agents Chemother. 51, 3367–3370.
Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis.CrossRef | 1:CAS:528:DC%2BD2sXhtVais7nO&md5=6a30db0f059b3a89ca67062f3a33dea1CAS | open url image1

Uyeturk, U., Firat, T., Cetinkaya, A., Kin Tekce, B., and Cakir, S. (2014). Protective effects of rosmarinic acid on doxorubicin-induced testicular damage. Chemotherapy 60, 7–12.
Protective effects of rosmarinic acid on doxorubicin-induced testicular damage.CrossRef | 1:CAS:528:DC%2BC2cXitVylsbjP&md5=00e4504c2be8021a34f3903a5d986240CAS | open url image1

Zheng, R.-L., and Zhang, H. (1997). Effects of ferulic acid on fertile and asthenozoospermic infertile human sperm motility, viability, lipid peroxidation, and cyclic nucleotides. Free Radic. Biol. Med. 22, 581–586.
Effects of ferulic acid on fertile and asthenozoospermic infertile human sperm motility, viability, lipid peroxidation, and cyclic nucleotides.CrossRef | 1:CAS:528:DyaK2sXntlOqsw%3D%3D&md5=cb223b52a7f422342f281dccd6122f32CAS | open url image1



Export Citation