Abstract
Purpose
Methotrexate (MTX) therapy is widely used in treatment of different types of diseases including inflammatory diseases, autoimmune disorders, and cancer. However, most of patients respond well to MTX, they suffer from multiple side effects including severe anorexia. Omega-3 fatty acid possesses many beneficial biological activities. Therefore, the objective of our study is to explore the effect of the combined modality of omega-3 (400 mg/kg/day) in MTX-induced anorexia in rats.
Methods
The effect of MTX alone and in combination with omega-3 on the body weight, ghrelin hormone level, histopathological findings of taste buds and hypothalamus and POMC gene expression were investigated.
Results
Interestingly, the capability of omega-3 to overcome the anorexic effect of MTX could be manifested by controlling weight loss, increasing serum HDL, elevating the ghrelin level as well as reducing both lesions within taste buds and hypothalamus and hypothalamic POMC gene expression.
Conclusions
our findings revealed that the omega-3 might be used as a complementary supplement during the MTX therapy to ameliorate its anorexic effect.
Similar content being viewed by others
References
T.G. Benedek, Methotrexate: from its introduction to non-oncologic therapeutics to anti-TNF-alpha. Clin. Exp. Rheumatol. 28(61), S3–S8 (2010).
R. Raghu Nadhanan, J. Skinner, R. Chung, Y.W. Su, P.R. Howe, C.J. Xian, Supplementation with fish oil and genistein, individually or in combination, protects bone against the adverse effects of methotrexate chemotherapy in rats. PloS ONE 8(8), e71592 (2013). https://doi.org/10.1371/journal.pone.0071592
S. Pirkmajer, S.S. Kulkarni, R.Z. Tom, F.A. Ross, S.A. Hawley, D.G. Hardie, J.R. Zierath, A.V. Chibalin, Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation. Diabetes 64(2), 360–369 (2015). https://doi.org/10.2337/db14-0508
R. Heidari, A. Ahmadi, H. Mohammadi, M.M. Ommati, N. Azarpira, H. Niknahad, Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomedicine Pharmacother. 107, 834–840 (2018). https://doi.org/10.1016/j.biopha.2018.08.050
Clavo, B., Rodriguez-Esparragon, F., Rodriguez-Abreu, D., Martinez-Sanchez, G., Llontop, P., Aguiar-Bujanda, D., Fernandez-Perez, L., Santana-Rodriguez, N., Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants 8(12), (2019). https://doi.org/10.3390/antiox8120588
M. Francois, K. Takagi, R. Legrand, N. Lucas, S. Beutheu, C. Bole-Feysot, A. Cravezic, N. Tennoune, J.C. do Rego, M. Coeffier, A. Inui, P. Dechelotte, S.O. Fetissov, Increased Ghrelin but low ghrelin-reactive immunoglobulins in a rat model of methotrexate chemotherapy-induced anorexia. Front. Nutr. 3, 23 (2016). https://doi.org/10.3389/fnut.2016.00023
Edwards, A., Abizaid, A.: Clarifying the Ghrelin system’s ability to regulate feeding behaviours despite enigmatic spatial separation of the GHSR and its endogenous Ligand. Int. J Mol Sci 18(4), (2017). https://doi.org/10.3390/ijms18040859
B. Fu, N. Wang, H.Y. Tan, S. Li, F. Cheung, Y. Feng, Multi-component herbal products in the prevention and treatment of chemotherapy-associated toxicity and side effects: a review on experimental and clinical evidences. Front. Pharmacol. 9, 1394 (2018). https://doi.org/10.3389/fphar.2018.01394
Y. Shiomi, Y. Ohira, M. Yoshimura, T. Ozaki, M. Takei, T. Tanaka, Z-505 hydrochloride ameliorates chemotherapy-induced anorexia in rodents via activation of the ghrelin receptor, GHSR1a. Eur. J. Pharmacol. 818, 148–157 (2018). https://doi.org/10.1016/j.ejphar.2017.10.047
S.P. Kalra, P.S. Kalra, Y. Neuropeptide, Endocrine 22(1), 49–55 (2003). https://doi.org/10.1385/ENDO:22:1:49
E. Qualls-Creekmore, H. Munzberg, Modulation of feeding and associated behaviors by lateral hypothalamic circuits. Endocrinology 159(11), 3631–3642 (2018). https://doi.org/10.1210/en.2018-00449
C. McGlory, P.C. Calder, E.A. Nunes, The influence of Omega-3 fatty acids on skeletal muscle protein turnover in health, disuse, and disease. Front. Nutr. 6, 144 (2019). https://doi.org/10.3389/fnut.2019.00144
C. Kilkenny, W.J. Browne, I.C. Cuthill, M. Emerson, D.G. Altman, Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J. Pharmacol. Pharmacother. 1(2), 94–99 (2010). https://doi.org/10.4103/0976-500x.72351
S.A. Yoon, J.R. Choi, J.O. Kim, J.Y. Shin, X. Zhang, J.H. Kang, Influence of reduced folate carrier and dihydrofolate reductase genes on methotrexate-induced cytotoxicity. Cancer Res. Treat.: Off. J. Korean Cancer Assoc. 42(3), 163–171 (2010). https://doi.org/10.4143/crt.2010.42.3.163
S.M. Abdel-Maksoud, S.I. Hassanein, N.A. Gohar, S.M.M. Attia, M.Z. Gad, Investigation of brain-derived neurotrophic factor (BDNF) gene expression in hypothalamus of obese rats: Modulation by omega-3 fatty acids. Nutritional Neurosci. 20(8), 443–448 (2017). https://doi.org/10.1080/1028415x.2016.1180859
Bancroft, J. D., & Gamble, M. Theory and practice of histological techniques, 6th edn. (Churchill Livingstone, Elsevier, 2008)
R.M. Khalil, W.S. Abdo, A. Saad, E.G. Khedr, Muscle proteolytic system modulation through the effect of taurine on mice bearing muscular atrophy. Mol. Cell. Biochem. 444(1–2), 161–168 (2018)
K. Fearon, F. Strasser, S.D. Anker, I. Bosaeus, E. Bruera, R.L. Fainsinger, A. Jatoi, C. Loprinzi, N. MacDonald, G. Mantovani, M. Davis, M. Muscaritoli, F. Ottery, L. Radbruch, P. Ravasco, D. Walsh, A. Wilcock, S. Kaasa, V.E. Baracos, Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12(5), 489–495 (2011). https://doi.org/10.1016/s1470-2045(10)70218-7
H. Suzuki, A. Asakawa, H. Amitani, N. Nakamura, A. Inui, Cancer cachexia-pathophysiology and management. J. Gastroenterol. 48(5), 574–594 (2013). https://doi.org/10.1007/s00535-013-0787-0
A.A. de Araújo, P.B. Borba, F.H.D. de Souza, A.C. Nogueira, T.S. Saldanha, T.E.F. Araújo, A.I. da Silva, R.F. de Araújo Júnior, In a methotrexate-induced model of intestinal mucositis, olmesartan reduced inflammation and induced enteropathy characterized by severe diarrhea, weight loss, and reduced sucrose activity. Biol. Pharm. Bull. 38(5), 746–752 (2015)
I.M. Berquin, I.J. Edwards, Y.Q. Chen, Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett. 269(2), 363–377 (2008)
K. Werner, D. Kullenberg de Gaudry, L.A. Taylor, T. Keck, C. Unger, U.T. Hopt, U. Massing, Dietary supplementation with n-3-fatty acids in patients with pancreatic cancer and cachexia: marine phospholipids versus fish oil—a randomized controlled double-blind trial. Lipids Health Dis. 16(1), 104 (2017). https://doi.org/10.1186/s12944-017-0495-5
B.A. Mhatre, T. Marar, Protective effect of Morinda citrifolia L.(fruit extract) on methotrexate-induced toxicities—hematological and biochemical studies. Cogent Biol. 2(1), 1207879 (2016)
F. Doostan, R. Vafafar, P. Zakeri-Milani, A. Pouri, R. Amini Afshar, M. Mesgari Abbasi, Effects of pomegranate (Punica Granatum L.) seed and peel methanolic extracts on oxidative stress and lipid profile changes induced by methotrexate in rats. Adv. Pharm. Bull. 7(2), 274–269 (2017). https://doi.org/10.15171/apb.2017.032
M. Studer, M. Briel, B. Leimenstoll, T.R. Glass, H.C. Bucher, Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch. Intern. Med. 165(7), 725–730 (2005)
A. Lewis, S. Lookinland, R.L. Beckstrand, M.E. Tiedeman, Treatment of hypertriglyceridemia with omega‐3 fatty acids: a systematic review. J. Am. Acad. Nurse Pract. 16(9), 384–395 (2004)
H. Yanai, Y. Masui, H. Katsuyama, H. Adachi, A. Kawaguchi, M. Hakoshima, Y. Waragai, T. Harigae, A. Sako, An improvement of cardiovascular risk factors by omega-3 polyunsaturated fatty acids. J. Clin. Med. Res. 10(4), 281–289 (2018). https://doi.org/10.14740/jocmr3362w
Y. Shanado, M. Kometani, H. Uchiyama, S. Koizumi, N. Teno, Lysophospholipase I identified as a ghrelin deacylation enzyme in rat stomach. Biochemical Biophys. Res. Commun. 325(4), 1487–1494 (2004). https://doi.org/10.1016/j.bbrc.2004.10.193
J. Yang, M.S. Brown, G. Liang, N.V. Grishin, J.L. Goldstein, Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132(3), 387–396 (2008). https://doi.org/10.1016/j.cell.2008.01.017
H. Takeda, C. Sadakane, T. Hattori, T. Katsurada, T. Ohkawara, K. Nagai, M. Asaka, Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 134(7), 2004–2013 (2008). https://doi.org/10.1053/j.gastro.2008.02.078
T. Ohno, M. Yanai, H. Ando, Y. Toyomasu, A. Ogawa, H. Morita, K. Ogata, E. Mochiki, T. Asao, H. Kuwano, Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans. Clin. Exp. Gastroenterol. 4, 291–296 (2011). https://doi.org/10.2147/ceg.s26297
Y. Hiura, S. Takiguchi, K. Yamamoto, T. Takahashi, Y. Kurokawa, M. Yamasaki, K. Nakajima, H. Miyata, Y. Fujiwara, M. Mori, K. Kangawa, Y. Doki, Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients: a prospective, randomized, placebo-controlled phase 2 study. Cancer 118(19), 4785–4794 (2012). https://doi.org/10.1002/cncr.27430
Y. Yanagimoto, S. Takiguchi, Y. Miyazaki, T. Makino, T. Takahashi, Y. Kurokawa, M. Yamasaki, H. Miyata, K. Nakajima, H. Hosoda, K. Kangawa, M. Mori, Y. Doki, Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial. Br. J. Cancer 114(12), 1318–1325 (2016). https://doi.org/10.1038/bjc.2016.160
A.A. Sneddon, D.V. Rayner, S.E. Mitchell, S. Bashir, J.H. Ha, K.W. Wahle, A.C. Morris, L.M. Williams, Dietary supplementation with conjugated linoleic acid plus n-3 polyunsaturated fatty acid increases food intake and brown adipose tissue in rats. Nutrients 1(2), 178–196 (2009). https://doi.org/10.3390/nu1020178
P.R. Burghardt, E.S. Kemmerer, B.J. Buck, A.J. Osetek, C. Yan, L.G. Koch, S.L. Britton, S.J. Evans, Dietary n-3:n-6 fatty acid ratios differentially influence hormonal signature in a rodent model of metabolic syndrome relative to healthy controls. Nutr. Metab. 7(1), 53 (2010). https://doi.org/10.1186/1743-7075-7-53
J.L. Stevenson, C.M. Paton, J.A. Cooper, Hunger and satiety responses to high-fat meals after a high-polyunsaturated fat diet: a randomized trial. Nutrition 41, 14–23 (2017). https://doi.org/10.1016/j.nut.2017.03.008
O. Kuduban, M.R. Mazlumoglu, S.D. Kuduban, E. Erhan, N. Cetin, O. Kukula, O. Yarali, F.K. Cimen, M. Cankaya, The effect of hippophae rhamnoides extract on oral mucositis induced in rats with methotrexate. J. Appl. oral. Sci. 24(5), 423–430 (2016). https://doi.org/10.1590/1678-775720160139
D. Renard, R. Westhovens, E. Vandenbussche, R. Vandenberghe, Reversible posterior leucoencephalopathy during oral treatment with methotrexate. J. Neurol. 251(2), 226–228 (2004). https://doi.org/10.1007/s00415-004-0287-5
F. Celik, C. Gocmez, M. Bozkurt, I. Kaplan, K. Kamasak, E. Akil, E. Dogan, A. Guzel, E. Uzar, Neuroprotective effects of carvacrol and pomegranate against methotrexate-induced toxicity in rats. Eur. Rev. Med. Pharmacol. Sci. 17(22), 2988–2993 (2013)
J. Wang, C. Chen, R.-Y. Wang, Influence of short- and long-term treadmill exercises on levels of ghrelin, obestatin and NPY in plasma and brain extraction of obese rats. Endocrine 33(1), 77–83 (2008). https://doi.org/10.1007/s12020-008-9056-z
M. López, S. Tovar, M.J. Vázquez, L.M. Williams, C. Diéguez, Peripheral tissue-brain interactions in the regulation of food intake. Proc. Nutr. Soc. 66(1), 131–155 (2007). https://doi.org/10.1017/s0029665107005368
J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, I. Wakabayashi, Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 50(11), 2438–2443 (2001). https://doi.org/10.2337/diabetes.50.11.2438
M.A. Cowley, R.G. Smith, S. Diano, M. Tschöp, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, L.M. Garcia-Segura, E.A. Nillni, P. Mendez, M.J. Low, P. Sotonyi, J.M. Friedman, H. Liu, S. Pinto, W.F. Colmers, R.D. Cone, T.L. Horvath, The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37(4), 649–661 (2003). https://doi.org/10.1016/s0896-6273(03)00063-1
C.F. Elias, C. Aschkenasi, C. Lee, J. Kelly, R.S. Ahima, C. Bjorbaek, J.S. Flier, C.B. Saper, J.K. Elmquist, Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23(4), 775–786 (1999). https://doi.org/10.1016/s0896-6273(01)80035-0
A.P. Coll, Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential? Clin. Sci. 113(4), 171–182 (2007). https://doi.org/10.1042/cs20070105
B. Dziedzic, J. Szemraj, J. Bartkowiak, A. Walczewska, Various dietary fats differentially change the gene expression of neuropeptides involved in body weight regulation in rats. J. Neuroendocrinol. 19(5), 364–373 (2007). https://doi.org/10.1111/j.1365-2826.2007.01541.x
L.F. Nascimento, G.F. Souza, J. Morari, G.O. Barbosa, C. Solon, R.F. Moura, S.C. Victório, L.M. Ignácio-Souza, D.S. Razolli, H.F. Carvalho, L.A. Velloso, n-3 fatty acids induce neurogenesis of predominantly POMC-expressing cells in the hypothalamus. Diabetes 65(3), 673–686 (2016). https://doi.org/10.2337/db15-0008
S. Ma, Y. Ge, X. Gai, M. Xue, N. Li, J. Kang, J. Wan, J. Zhang, Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus. Neurosci. Lett. 611, 28–32 (2016). https://doi.org/10.1016/j.neulet.2015.11.029
Funding
The research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors funded the research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Mostafa, H., Barakat, L., Abdo, W.S. et al. Omega-3 offers better hypothalamus protection by decreasing POMC expression and elevating ghrelin hormone: a prospective trial to overcome methotrexate-induced anorexia. Endocrine 69, 358–367 (2020). https://doi.org/10.1007/s12020-020-02342-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-020-02342-0