Ethics code: AUERC/1259


XML Persian Abstract Print


1- Department of Anatomy, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria , amedunath11@gmail.com
2- Department of Anatomy, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
Abstract:   (138 Views)

Background: The hippocampus, a key region for learning and memory, is influenced by hormonal treatments, which have been shown to alter cognitive functions and hippocampal microstructure. This study investigates the effects of ethinylestradiol (EE) and levonorgestrel (LNG) administration on cognitive flexibility, neurochemical changes, and structural alterations in the rat hippocampus.
Methods: Forty adolescent female Wistar rats were divided into four groups (n=10). The control group (Group A) received only distilled water for 21 days. Groups B, C, and D were administered combined oral contraceptives (COC) containing EE and LNG at doses of 0.03 mg/kg and 0.15 mg/kg, respectively, for 7, 14, and 21 days. Y-maze tests were performed to assess learning and memory. A histological study of the hippocampus was conducted using H&E staining. The levels of dopamine, acetylcholinesterase, malondialdehyde, superoxide dismutase, and interleukin-1β were subsequently assessed using biochemical techniques.
Results: Administration of EE/LNG (21 days) significantly enhanced cognitive flexibility, as shown by a higher alternation percentage in the Y-maze test. Neurochemical analysis revealed increased dopamine levels, oxidative stress (MDA), and decreased antioxidant activity (SOD) with prolonged treatment. Acetylcholinesterase activity was significantly higher in the 21-day group. Hippocampal pyramidal cell counts increased significantly in the EE/LNG 21 days compared to the control for both CA1 (183,076 ± 7,900) and CA3 (284,234 ± 9,205) regions with treatment duration. Histopathological analysis showed distorted dentate gyrus (DG) regions.
Conclusion: Prolonged EE/LNG treatment enhances cognitive flexibility in rats, likely mediated by neurochemical and structural changes in the hippocampus. However, the associated oxidative stress and alterations in acetylcholinesterase activity, along with observed histopathological changes, highlight potential risks to hippocampal integrity and neurogenesis, warranting further investigation into the long-term implications of such treatments.

 

Full-Text [PDF 577 kb]   (19 Downloads) |   |   Full-Text (HTML)  (11 Views)  
Article Type: Research | Subject: Neuroscience

References
1. Ando H, Ukena K, Nagata S. Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research. Academic Press;2021. [View at Publisher] [DOI] [Google Scholar]
2. Speranza L, Di Porzio U, Viggiano D, de Donato A, Volpicelli F. Dopamine: The neuromodulator of long-term synaptic plasticity, reward and movement control. Cells. 2021;10(4):735. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Kienast T, Heinz A. Dopamine and the diseased brain. CNS Neurol Disord Drug Targets. CNS Neurol Disord Drug Targets. 2006;5(1):109-31. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Olivares-Hernández A, Figuero-Pérez L, Cruz-Hernandez JJ, Sarmiento RG, Usategui-Martin R, Miramontes-González JP. Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications. Biomolecules. 2021;11(2):254. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Juárez Olguín H, Calderón Guzmán D, Hernández García E, Barragán Mejía G. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxid Med Cell Longev. 2015;2016:9730467. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Quinn KM, Roberts L, Cox AJ, Borg DN, Pennell EN, McKeating DR, et al. Blood oxidative stress biomarkers in women: influence of oral contraception, exercise, and N-acetylcysteine. Eur J Appl Physiol. 2022;122(8):1949-64. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Cauci S, Xodo S, Buligan C, Colaninno C, Barbina M, Barbina G, et al. Oxidative Stress Is Increased in Combined Oral Contraceptives Users and Is Positively Associated with High-Sensitivity C-Reactive Protein. Molecules. 2021;26(4):1070. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. Meiser J, Weindl D, Hiller K. Complexity of dopamine metabolism. Cell Commun Signal. 2013;11(1):34. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. Miyazaki I, Asanuma M. Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Medica Okayama. 2008;62(3):141-50. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. Jenner P, Hunot, Olanow, Beal, Kordower, Tatton, et al. Oxidative stress in Parkinson's disease. Ann Neurol . 2003;53(S3):S26-36. [View at Publisher] [DOI] [PMID] [Google Scholar]
11. Shaftel SS, Griffin WST, Kerry OM. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008;5:7. [View at Publisher] [DOI] [PMID] [Google Scholar]
12. Das UN. Acetylcholinesterase and butyrylcholinesterase as possible markers of low-grade systemic inflammation. Med Sci Monit. 2007;13(12):RA214-21. [View at Publisher] [PMID] [Google Scholar]
13. Pollak Y, Gilboa A, Ben-Menachem O, Ben-Hur T, Soreq H, Yirmiya R. Acetylcholinesterase inhibitors reduce brain and blood interleukin-1β production. Ann Neurol. 2005;57(5):741-5. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Kabiersch A, Furukawa H, Rey A Del, Besedovsky HO. Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann N Y Acad Sci. 1998:840:123-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Amedu NO, Obu MO. Atrazine-induced Hippocampal Degeneration and Behavioral Deficits in Wistar Rats: Mitigative role of avocado oil. Iranian Journal of Toxicology. 2022;16(3):211-20. [View at Publisher] [DOI] [Google Scholar]
16. Simone J, Bogue EA, Bhatti DL, Day LE, Farr NA, Grossman AM, et al. Ethinyl estradiol and levonorgestrel alter cognition and anxiety in rats concurrent with a decrease in tyrosine hydroxylase expression in the locus coeruleus and brain-derived neurotrophic factor expression in the hippocampus. Psychoneuroendocrinology. 2015;62:265-78. [View at Publisher] [DOI] [PMID] [Google Scholar]
17. Nwakanma A, Ekanem T, Eluwa M, Elemuo C, Ekong M. Ethinyl estadiol/progestin oral contraceptives depress spatial learning and dysregulate hippocampal CA3 microstructure: Implications for behavioral-cognitive effects of chronic contraceptive use? Acta Medica Bulgarica. 2021;48(2):53-61. [View at Publisher] [DOI] [Google Scholar]
18. Lacasse JM, Boulos V, Fisher C, Hamilton S, Heron M, Mac Cionnaith CE, et al. Combined effects of the contraceptive hormones, ethinyl estradiol and levonorgestrel, on the use of place and response memory in gonadally-intact female rats. Psychoneuroendocrinology. 2023:147:105974. [View at Publisher] [DOI] [PMID] [Google Scholar]
19. Jones-Bolin S. Guidelines for the care and use of laboratory animals in biomedical research. Curr Protoc Pharmacol. 2012;2012:Appendix 4:Appendix 4B. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. Gage GJ, Kipke DR, Shain W. Whole animal perfusion fixation for rodents. J Vis Exp. 2012;(65):3564. [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Suvarna SK, Layton C, Bancroft JD. Bancroft's Theory and Practice of Histological Techniques. 8th ed. UK:Elsevier Health Sci;2018. [View at Publisher] [Google Scholar]
22. Gao H, Tian Y, Wang W, Yao D, Zheng T, Meng Q. Levels of interleukin-6, superoxide dismutase and malondialdehyde in the lung tissue of a rat model of hypoxia-induced acute pulmonary edema. Exp Ther Med. 2016;11(3):993-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Fajrilah BR, Indrayani UD, Djamâ€TMan Q. The Effect of Honey on Plasma Malondialdehyde (MDA) Level onAlloxan-Induced hyperglycemic Rats An Experimental studies in rats Galur Wistar White Males. Sains Medika : Jurnal Kedokteran dan Kesehatan. 2013;5(2). [View at Publisher] [DOI] [Google Scholar]
24. Wang HB, Li Y, Dong GL, Gan T, Liu YM. A convenient and label-free colorimetric assay for dopamine detection based on the inhibition of the Cu(II)-catalyzed oxidation of a 3,3′,5,5′-tetramethylbenzidine-H2O2 system. New Journal of Chemistry. 2017;41(23). [View at Publisher] [DOI] [Google Scholar]
25. Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7(2):88-95. [View at Publisher] [DOI] [PMID] [Google Scholar]
26. Miki T, Satriotomo I, Li HP, Matsumoto Y, Gu H, Yokoyama T, et al. Application of the physical disector to the central nervous system: estimation of the total number of neurons in subdivisions of the rat hippocampus. Anat Sci Int. 2005;80(3):153-62. [View at Publisher] [DOI] [PMID] [Google Scholar]
27. Baudonnat M, Huber A, David V, Walton ME. Heads for learning, tails for memory: Reward, reinforcement and a role of dopamine in determining behavioral relevance across multiple timescales. Front Neurosci. 2013:7:175. [View at Publisher] [DOI] [PMID] [Google Scholar]
28. Kourosh-Arami M, Komaki A, Zarrindast MR. Dopamine as a Potential Target for Learning and Memory: Contributing to Related Neurological Disorders. CNS Neurol Disord Drug Targets. 2023;22(4):558-76. [View at Publisher] [DOI] [PMID] [Google Scholar]
29. Abraham AD, Neve KA, Lattal KM. Dopamine and extinction: A convergence of theory with fear and reward circuitry. Neurobiol Learn Mem. 2014:108:65-77. [View at Publisher] [DOI] [PMID] [Google Scholar]
30. Huang Q, Liao C, Ge F, Ao J, Liu T. Acetylcholine bidirectionally regulates learning and memory. Journal of Neurorestoratology. 2022;10(2). [View at Publisher] [DOI] [Google Scholar]
31. Micheau J, Marighetto A. Acetylcholine and memory: A long, complex and chaotic but still living relationship. Behav Brain Res. 2011;221(2):424-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
32. Kraeuter AK, Guest PC, Sarnyai Z. The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice. Methods Mol Biol. 2019:1916:105-11. [View at Publisher] [DOI] [PMID] [Google Scholar]
33. Golub M. UC Davis - Y-Maze. v1. 2019. [Protocol] [View at Publisher] [DOI]
34. Wusu AD, Bankole HA, Fatai AA, Kanmodi RI, Obasieke PE, Wusu TD. Combined Oral Administration of Ethinylestradiol and Levonorgestrel Alters the Expression of Antioxidant and Apoptotic Markers in Female Rats. 2021;16(1). [View at Publisher] [Google Scholar]
35. Gajtkó A, Bakk E, Hegedűs K, Ducza L, Holló K. IL-1β Induced Cytokine Expression by Spinal Astrocytes Can Play a Role in the Maintenance of Chronic Inflammatory Pain. Front Physiol. 2020:11:543331. [View at Publisher] [DOI] [PMID] [Google Scholar]
36. Srinivasan D, Yen JH, Joseph DJ, Friedman W. Cell type-specific interleukin-1beta signaling in the CNS. J Neurosci. 2004;24(29):6482-8. [View at Publisher] [DOI] [PMID] [Google Scholar]
37. Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1β is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci. 1998;18(8):2974-81. [View at Publisher] [DOI] [PMID] [Google Scholar]
38. Palin K, Bluthé RM, Verrier D, Tridon V, Dantzer R, Lestage J. Interleukin-1β mediates the memory impairment associated with a delayed type hypersensitivity response to bacillus Calmette-Guérin in the rat hippocampus. Brain Behav Immun. 2004;18(3):223-30. [View at Publisher] [DOI] [PMID] [Google Scholar]
39. Azzubaidi MS, Saxena A, Talib NA. Quantifying dorsal Hippocampal CA-1 pyramidal cells in rats: rules to light microscope based estimation. Malaysian Journal of Microscopy. 2013;9(1). [View at Publisher] [Google Scholar]

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2025 CC BY-NC 4.0 | Journal of Clinical and Basic Research

Designed & Developed by : Yektaweb

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).