Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue

Mustafa Ermiş; Erol Karakaş; Hanifi Erol; Recai Aci; Furkan Ümit; Gülay Çiftci

doi:10.35229/jaes.1801041

TR EN

Letrozol Uygulamasının Rat Serum ve Beyin Dokusunda Metabolik, İnflamatuar ve Oksidatif Yanıtlar Üzerine Etkileri

Öz

Letrozol, östrojen sentezini azaltan ve meme kanseri tedavisinde kullanılan bir ilaçtır. Uzun süreli kullanımı sistemik ve nörolojik etkiler oluşturabilir. Bu çalışmada, Letrozol uygulanan dişi ratlarda biyokimyasal, inflamatuar ve nörolojik parametreler incelendi. Çalışma, 6’şar ratlı kontrol ve Letrozol (1 mg/kg, 21 gün) gruplarından oluştu. 21. gün sonunda ratlardan kan ve beyin dokusu örnekleri alındı. Proinflamatuar sitokinler ve Aβ₁₋₄₀ düzeyleri ELISA ile toplam antioksidan (TAS) ve toplam oksidan (TOS) düzeyleri Relassay kitleriyle, biyokimyasal parametreler ve mineraller ise otoanalizörle ölçüldü. Analizlerde, Letrozol grubunda total protein, albümin, glukoz ve serum sodyum düzeylerinde anlamlı artış; ürede ise azalma saptandı (P<0.05). Lipid profilindeki değişiklikler anlamlı değildi (P>0.05). Beyin dokusunda trigliserit ve total kolesterol düzeyleri anlamlı arttı (P<0.05). Serumda IL-1α, IL-1β, TNF-α, NF-κB ve Aβ₁₋₄₀ düzeyleri artarken (P<0.01), TAS azaldı (P<0.05). Beyin dokusunda trigliserit ve total kolesterol düzeylerinde anlamlı artış gözlendi (P<0.05). Serumda IL-1α, IL-1β, TNF-α, NF-κB ve Aβ₁₋₄₀ düzeyleri artarken (P<0.01), TAS azaldı (P<0.05). Beyin dokusunda ise yalnızca IL-1β ve NF-κB düzeylerinde anlamlı artış saptandı (P<0.05). Sonuç olarak, Letrozol kullanımının sistemik inflamasyon ve oksidatif stresi artırdığı; ancak beyin üzerindeki etkilerinin daha sınırlı olduğu görüldü. Artan amiloid beta düzeyleri ise nöroinflamasyon ve potansiyel nörodejeneratif risklerin göstergesi olarak değerlendirildi.

Anahtar Kelimeler

Aβ₁₋₄₀, beyin, inflamasyon, letrozole, oksidatif stres, rat

Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue

Öz

Letrozole is a drug that reduces estrogen synthesis and is used in the treatment of breast cancer. Its long-term use may cause systemic and neurological effects. In this study, biochemical, inflammatory, and neurological parameters were examined in female rats administered Letrozole. The study consisted of control and Letrozole groups (1 mg/kg for 21 days), each with 6 rats. On day 21, blood and brain tissue samples were collected from the rats. Proinflammatory cytokines and Aβ₁₋₄₀ levels were measured by ELISA, total antioxidant status (TAS) and total oxidant status (TOS) levels by Relassay kits, and biochemical parameters and minerals by an autoanalyzer. Analyses showed significant increases in total protein, albumin, glucose, and serum sodium levels, and a decrease in urea in the Letrozole group (P<0.05). Changes in the lipid profile were not significant (P>0.05). Triglyceride and total cholesterol levels in brain tissue increased significantly (P<0.05). Serum levels of IL-1α, IL-1β, TNF-α, NF-κB, and Aβ₁₋₄₀ increased (P<0.01), while TAS decreased (P<0.05). In the brain, only IL-1β and NF-κB levels were elevated (P<0.05). In conclusion, Letrozole increases systemic inflammation and oxidative stress, with more limited effects on the brain. The elevated amyloid beta levels indicate neuroinflammation and potential neurodegenerative risks.

Anahtar Kelimeler

brain,, inflammation, letrozole, Aβ₁₋₄₀, oxidative stress, rat

Kaynakça

Agarwal, A., Aponte-Mellado, A., Premkumar, B.J., Shaman, A., & Gupta, S. (2012). The effects of oxidative stress on female reproduction: A review. Reprod. Biol. Endocrinol., 10, 49. https://doi.org/10.1186/1477-7827-10-49
Al-Harbi, L.N., AlSedairy, S.A., Alshammari, G.M., Binobead, M.A., & Arzoo, S. (2025). Protective effect of marjoram against letrozole-induced ovarian damage in rats with polycystic ovarian syndrome entails activation of Nrf2 and suppression of NF-κB. Pharmaceuticals, 18(9),1291. https://doi.org/10.3390/ph18091291
Allan, S.M., Tyrrell, P.J., & Rothwell, N.J. (2005). Interleukin-1 and neuronal injury. Nat. Rev. Immunol., 5(8), 629-40. https://doi.org/10.1038/nri1664
Arevalo, M.A., Azcoitia, I. & Garcia-Segura, L.M. (2015). The neuroprotective actions of oestradiol and oestrogen receptors. Nat. Rev. Neurosci., 16(1), 17-29. https://doi.org/10.1038/nrn3856
Baravalle, C., Guazzone, V.A., Jarazo-Dietrich, S., Theas, M.S., & Lustig, L. (2006). Effect of letrozole on rat estrous cycle and ovarian morphology. Reprod. Toxicol., 21(1), 52-8.
Baravalle, C., Salvetti, N.R., Mira, G.A., Pezzone, N., & Ortega, H.H. (2006). Microscopic characterization of follicular structures in letrozole-induced polycystic ovarian syndrome in Archives of Medical Research, 37(7), 830-9. https://doi.org/10.1016/j.arcmed.2006.03.005
Behl, C. (2002). Oestrogen and neuroprotection. Nature Reviews Neuroscience, 3(6), 433-42. https://doi.org/10.1038/nrn846
Biswas, S.K. (2016). Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxid. Med. Cell. Longev., 2016, 5698931. https://doi.org/10.1155/2016/5698931
Brinton, R.D. (2008). Estrogen-induced plasticity from cells to circuits: Predictions for cognitive function. Trend. Pharmacol. Sci., 30(4), 212-22. https://doi.org/10.1016/j.tips.2008.12.006
Butterfield, D.A. & Halliwell, B. (2019). Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci., 20(3), 148-60. https://doi.org/0.1038/s41583-019-0132-6

Erel, O. (2004). A novel automated method to measure total antioxidant response against potent free radical reactions. Clin. Biochem., 37(2), 112-19. https://doi.org/10.1016/j.clinbiochem.2003.10.01 4
Erel, O. (2005). A new automated colorimetric method for measuring total oxidant status. Clin. Biochem., 38(12), 1103-11. https://doi.org/10.1016/j.clinbiochem.2005.08.00 8
Ermiş, M., & Çiftci, G. (2024). Role of curcumin on beta- amyloid protein, tau protein, and biochemical and oxidative changes in streptozotocin-induced diabetic rats. Naunyn-Schmiedeberg's Arch. Pharmacol., 397(12), 9833-44. https://doi.org/10.1007/s00210-024-03231-3
Gibb, F.W., Homer, N.Z.M., Faqehi, A.M.M., Upreti, R., Livingstone, D.E., McInnes, K.J., Andrew, R., & Walker, B.R. (2016). Aromatase inhibition reduces insulin sensitivity in healthy men. The Journal of Clinical Endocrinology & Metabolism, 101(5), 2040-6. https://doi.org/10.1210/jc.2015-4146
Glass, C.K. & Saijo, K. (2010). Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol., 10(5), 365-76. https://doi.org/10.1038/nri2748
Goss, P. E., Ingle, J.N., Martino, S., Robert, N.J., Muss, H.B., Piccart, M.J., Castiglione, M., Tu, D., Shepherd, L.E., Pritchard, K.I., Livingston, R.B., Davidson, N.E., Norton, L., Perez, E.A., Abrams, J.S., Therasse, P., Palmer, M.J., & Pater, J.L. (2003). A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New England Journal of Medicine, 349(19), 1793-802. https://doi.org/10.1056/NEJMoa032312
Grodin, J.M., Siiteri, P.K., & MacDonald, P.C. (1973). Source of estrogen production in postmenopausal women. J. Clin. Endocrinol. Metabol., 36(2), 207- 14. https://doi.org/10.1210/jcem-36-2-207
Heneka, M.T., Golenbock, D.T. & Latz, E. (2015). Innate immunity in Alzheimer’s disease. Nat. Immunol., 16(3), 229-36. https://doi.org/10.1038/ni.3102
Ibrahim, Y.F., Alorabi, M., Abdelzaher, W.Y., Toni, N.D., Thabet, K., Hegazy, A., Bahaa, H.A., Batiha, G.E., Welson, N.N., &Morsy, M.A. (2022). Diacerein ameliorates letrozole-induced polycystic ovarian syndrome in rats. Biomed. Pharmacother., 149, 112870. https://doi.org/10.1016/j.biopha.2022.112870
Kafali, H., Iriadam, M., Ozardalı, I., & Demir, N. (2004). Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch. Med. Res., 35(2), 103-8. https://doi.org/10.1016/j.arcmed.2003.10.005
Kaltschmidt, B., & Kaltschmidt, C. (2009). NF-κB in the nervous system. Cold Spring Harbor Perspect. Biol., 1(3), a001271. https://doi.org/10.1101/cshperspect.a001271
Kim, S.H., Han, K., Lee, Y.H., Lee, S.H., & Park, Y.M. (2016). C-peptide-based index is more related to incident type 2 diabetes in non-diabetic subjects than insulin-based index. Diabet. Metabol. J., 40(2), 140-7. https://doi.org/10.3803/EnM.2016.31.2.320
Krysiak, R., Kowalcze, K., & Okopień, B. (2020). Effects of an aromatase inhibitor on mineral homeostasis and calcium-regulating hormones in men with hypogonadism. Pharmacological Reports, 72(2), 407-12. https://doi.org/10.1007/s43440-020-00071
Lawrence, T. (2009). The nuclear factor NF-κB pathway in inflammation. Cold Spring Harbor Perspect. Biol., 1(6), a001651. https://doi.org/10.1101/cshperspect.a001651
Lee, J.H., Lee, S.R., Lee, S.J., Lee, H.Y., Lee, H.W., & Han, E.J. (2022). Letrozole accelerates metabolic remodeling through activation of glycolysis in cardiomyocytes: A role beyond hormone regulation. International Journal of Molecular Sciences, 23(1), 547. https://doi.org/10.3390/ijms23010547
Love, R.R., Mazess, R.B., Barden, H.S., Epstein, S., Newcomb, P.A., Jordan, V.C., & Carbone, P.P. (2005). Effects of tamoxifen on lipid profiles in postmenopausal women. Annal. Intern. Med., 122(9), 653-9. https://doi.org/10.1093/jnci/82.16.1327
Maddaloni, E., & Ceriello, A. (2022). C-peptide determination in the diagnosis of type of diabetes and its management: A clinical perspective. Diabetes, Obesity and Metabolism, 24(6), 1065- 76. https://doi.org/10.1111/dom.14785
Manneras, L., Cajander, S., Holmäng, A., Seleskog, J., Lystig, T.C., Lönn, M., Stener-Victorin, E., & Jansson, T. (2007). A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinol., 148(8), 3781-91. https://doi.org/10.1210/en.2007-0168
Mauvais-Jarvis, F. (2011). Estrogen and androgen receptors: Regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends in Endocrinology & Metabolism, 22(1), 24-33. https://doi.org/10.1016/j.tem.2010.10.002
Miller, A.H., & Raison, C.L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol., 16(1), 22-34. https://doi.org/10.1038/nri.2015.5
Moser, V.A., & Pike, C.J. (2016). Obesity and sex interact in the regulation of Alzheimer's disease. Neurosci. Biobehav. Rev., 67, 102-18. https://doi.org/10.1016/j.neubiorev.2015.08.021
Pant, U.D.K. (2007). Aromatase inhibitors: Past, present and future in breast cancer therapy. Medical Oncology, 24(2), 119-24. https://doi.org/10.1007/s12032-007-9019-x
Perry, V.H., & Holmes, C. (2014). Microglial priming in neurodegenerative disease. Nat. Rev. Neurol., 10(4), 217-24. https://doi.org/10.1038/nrneurol.2014.38
Shaftel, S.S., Griffin, W.S., & O'Banion, M.K. (2008). The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J. Neuroinflam., 5, 7. https://doi.org/10.1186/1742-2094-5-7
Siddiqui, S., Mateen, S., Ahmad, R., & Moin, S. (2022). A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS). J. Assist. Reprod. Genet., 39(12), 2439- 73. https://doi.org/10.1007/s10815-022-02625-7 Straub, R.H. (2007). The complex role of estrogens in inflammation. Endocr. Rev., 28(5), 521-74. https://doi.org/10.1210/er.2007-0001
Tomaszewska, E., Dobrowolski, P., Winiarska- Mieczan, A., Kwiecień, M., Tomczyk, A., Muszyński, S., & Świetlicka, I. (2020). Morphology and serum and bone tissue calcium and magnesium concentrations in the bones of male rats chronically treated with letrozole. Annals of Animal Science, 20(3), 973-87. https://doi.org/10.2478/aoas-2020-0028
Vaziri, N.D. & Rodríguez-Iturbe, B. (2006). Mechanisms of disease: Oxidative stress and inflammation in the pathogenesis of hypertension. Nat. Clin. Pract. Nephrol., 2, 582-93. https://doi.org/10.1038/ncpneph0283
Vegeto, E., Villa, A., Della Torre, S., Crippa, V., Rusmini, P., Cristofani, R., & Poletti, A. (2020). The role of estrogens in neuroinflammation and neurodegeneration. Front. Neuroendocrinol., 57, 100839. https://doi.org/10.1016/j.yfrne.2008.04.001
Wahren, J., Ekberg, K., Johansson, J., Henriksson, M., Pramanik, A., Johansson, B.L., Rigler, R., & Jörnvall, H. (2000). Role of C-peptide in human physiology. Amer. J. Physiol. Endocrinol. Metabol., 278(5), 759-68. https://doi.org/10.1152/ajpendo.2000.278.5.E759
Walsh, B.W., Schiff, I., Rosner, B., Greenberg, L., Ravnikar, V., & Sacks, F.M. (1991). Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. New England J. Med., 325(17), 1196-204. https://doi.org/10.1056/NEJM199110243251702
Wasan, K.M., Goss, P.E., Pritchard, P.H., Shepherd, L., Palmer, M.J., Liu, S., Tu, D., Ingle, J. N., Heath, M., DeAngelis, D., & Perez, E.A. (2005). The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). The Lancet Oncology, 6(5), 317-24. https://doi.org/10.1016/S1470-2045(05)70150-1
Xu, Y., Jiang, J., & Huang, J. (2017). Dose-dependent effects of estrogen on lipid metabolism in ovariectomized rats. Journal of Endocrinology, 234(2), 123-34. https://doi.org/10.1530/JOE-16- 0421
Xue, B., & Zhang, Z. (2022). Estrogen regulation of renal sodium transport and blood pressure control. Physiological Reports, 10(3), e15190. https://doi.org/10.14814/phy2.15190
Yao, J., Irwin, R.W., Zhao, L., Nilsen, J., Hamilton, R.T., & Brinton, R.D. (2010). Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer's disease. Proc. Nat. Acad. Sci. U.S.A., 106(34), 14670-75. https://doi.org/10.1073/pnas.0903563106
Yue, X., Lu, M., Lancaster, T., Cao, P., Honda, S., Staufenbiel, M., Harada, N., Zhong, Z., & Shen, Y. (2005). Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer’s disease animal model. Proceedings of the National Academy of Sciences of the United States of America, 102(52), 19198-203. https://doi.org/10.1073/pnas.0505203102
Zhao, L., & Brinton, R.D. (2007). Estrogen receptor alpha and beta differentially regulate intracellular Ca²⁺ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. Brain Res., 1172, 48-59. https://doi.org/10.1016/j.brainres.2007.06.092

Ayrıntılar

Birincil Dil

İngilizce

Konular

Veteriner Biyokimya

Bölüm

Araştırma Makalesi

Yazarlar

Mustafa Ermiş
0000-0003-2267-1238
Türkiye

Erol Karakaş
0000-0001-6050-6765
Türkiye

Hanifi Erol
0000-0001-8140-3108
Türkiye

Recai Aci
0000-0002-1517-3356
Türkiye

Furkan Ümit
0009-0004-3556-5519
Türkiye

Gülay Çiftci ^*
0000-0001-5384-2381
Türkiye

Yayımlanma Tarihi

7 Ocak 2026

Gönderilme Tarihi

13 Ekim 2025

Kabul Tarihi

12 Aralık 2025

Yayımlandığı Sayı

Yıl 2026 Sayı: 2026

DOI

https://doi.org/10.35229/jaes.1801041

IZ

https://izlik.org/JA26RL45FS

APA

Ermiş, M., Karakaş, E., Erol, H., Aci, R., Ümit, F., & Çiftci, G. (2026). Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue. Journal of Anatolian Environmental and Animal Sciences, 2026, 1-9. https://doi.org/10.35229/jaes.1801041

AMA

1.Ermiş M, Karakaş E, Erol H, Aci R, Ümit F, Çiftci G. Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue. Journal of Anatolian Environmental and Animal Sciences. 2026;(2026):1-9. doi:10.35229/jaes.1801041

Chicago

Ermiş, Mustafa, Erol Karakaş, Hanifi Erol, Recai Aci, Furkan Ümit, ve Gülay Çiftci. 2026. “Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue”. Journal of Anatolian Environmental and Animal Sciences, sy 2026: 1-9. https://doi.org/10.35229/jaes.1801041.

EndNote

Ermiş M, Karakaş E, Erol H, Aci R, Ümit F, Çiftci G (01 Ocak 2026) Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue. Journal of Anatolian Environmental and Animal Sciences 2026 1–9.

IEEE

[1]M. Ermiş, E. Karakaş, H. Erol, R. Aci, F. Ümit, ve G. Çiftci, “Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue”, Journal of Anatolian Environmental and Animal Sciences, sy 2026, ss. 1–9, Oca. 2026, doi: 10.35229/jaes.1801041.

ISNAD

Ermiş, Mustafa - Karakaş, Erol - Erol, Hanifi - Aci, Recai - Ümit, Furkan - Çiftci, Gülay. “Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue”. Journal of Anatolian Environmental and Animal Sciences. 2026 (01 Ocak 2026): 1-9. https://doi.org/10.35229/jaes.1801041.

JAMA

1.Ermiş M, Karakaş E, Erol H, Aci R, Ümit F, Çiftci G. Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue. Journal of Anatolian Environmental and Animal Sciences. 2026;:1–9.

MLA

Ermiş, Mustafa, vd. “Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue”. Journal of Anatolian Environmental and Animal Sciences, sy 2026, Ocak 2026, ss. 1-9, doi:10.35229/jaes.1801041.

Vancouver

1.Mustafa Ermiş, Erol Karakaş, Hanifi Erol, Recai Aci, Furkan Ümit, Gülay Çiftci. Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue. Journal of Anatolian Environmental and Animal Sciences. 01 Ocak 2026;(2026):1-9. doi:10.35229/jaes.1801041

JAES, 2016- 11.yıl

Letrozol Uygulamasının Rat Serum ve Beyin Dokusunda Metabolik, İnflamatuar ve Oksidatif Yanıtlar Üzerine Etkileri

Öz

Anahtar Kelimeler

Effects of Letrozole Administration on Metabolic, Inflammatory, and Oxidative Responses in Rat Serum and Brain Tissue

Öz

Anahtar Kelimeler

Kaynakça

Ayrıntılar

Birincil Dil

Konular

Bölüm

Yazarlar

Yayımlanma Tarihi

Gönderilme Tarihi

Kabul Tarihi

Yayımlandığı Sayı

DOI

IZ

Kaynak Göster