Research Article
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Effects of metformin in an experimental chronic unpredictable mild stress model

Year 2026, Volume: 30 Issue: 1, 171 - 185, 11.01.2026

Mehmet Haktan Ozsagır , Elif Beyzanur Polat , Özlem Tuğçe Çilingir Kaya , Aslı Aykaç , Dilek Özbeyli

https://doi.org/10.12991/jrespharm.1690442

Abstract

Prolonged interaction with challenging life situations is a well-recognised risk factor for depression, anxiety, and cognitive decline, particularly among menopausal women. This research aimed to assess the effects of metformin (MF) on anxiety-like behavioural changes, cognitive impairment, brain neuroplasticity, and apoptosis induced by chronic unpredictable mild stress (CUMS) in menopausal rats. To achieve this, we conducted the open field test (OFT) to measure anxiety- like behaviours and locomotor activity, the elevated plus- maze (EPM) to assess anxiety-like behaviour, and the novel object recognition test (NORT) to evaluate recognition memory. Additionally, we measured the levels of BDNF, SIRT 1, synaptophysin, and caspase-9 by ELISA in the hippocampus, prefrontal cortex (PFC), and amygdala. Our experimental groups were categorised into five groups, with six rats in each group, as follows: Control, ovariectomized (OVX), OVX+CUMS, OVX+MF, and OVX+CUMS+MF. Four weeks after the OVX, the CUMS protocol was implemented, and MF treatment commenced following CUMS and continued for 14 days. Chronic administration of MF improved recognition memory and anxiety levels in rats subjected to CUMS, as assessed by the NORT, OFT, and EPM. MF increased brain-derived neurotrophic factor, synaptophysin, and sirtuin1, key markers of neuroplasticity in specific brain regions. We also found that MF treatment reduced pro-apoptotic caspase-9 levels. Histopathological analysis of the hippocampal DG and prefrontal cortex indicated neurodegenerative changes such as pyknotic nuclei, cytoplasmic sparseness, widespread vacuolization, and perivascular and pericellular oedema in the OVX and OVX+CUMS groups. However, these pathological features were significantly diminished in the MF groups, resulting in better preservation of neuronal integrity, fewer pyknotic cells, and reduced vacuolization. In conclusion, metformin appears to be a beneficial therapeutic agent that enhances neural plasticity, decreases apoptosis, and improves recognition memory and anxiety- like behaviours induced by OVX+CUMS

Keywords

CUMS BDNF SIRT1 synaptophysin caspase-9 metformin brain rat

Supporting Institution

This study has been supported by Marmara University Scientific Research Projects Coordination Unit (BABKO) under grant number: 11465.

Project Number

TYL-2024-11465

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Year 2026, Volume: 30 Issue: 1, 171 - 185, 11.01.2026

Mehmet Haktan Ozsagır , Elif Beyzanur Polat , Özlem Tuğçe Çilingir Kaya , Aslı Aykaç , Dilek Özbeyli

https://doi.org/10.12991/jrespharm.1690442

Abstract

Project Number

TYL-2024-11465

References

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  • [2] Soares CN, Zitek B. Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability? J Psychiatry Neurosci. 2008; 33(4):331-343.
  • [3] Azarfarin M, Moradikor N, Salatin S, Sarailoo M, Dadkhah M. Stress-related neurodegenerative diseases: Molecular mechanisms implicated in neurodegeneration and therapeutic strategies. Prog Brain Res. 2025; 291:253-288. https://doi.org/10.1016/bs.pbr.2025.01.011.
  • [4] Kline SA, Mega MS. Stress-Induced Neurodegeneration: The Potential for Coping as Neuroprotective Therapy. Am J Alzheimers Dis Other Demen. 2020;35:1533317520960873. https://doi.org/10.1177/1533317520960873
  • [5] Lupien SJ, Juster RP, Raymond C, Marin MF. The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. Front Neuroendocrinol. 2018; 49:91-105. https://doi.org/10.1016/j.yfrne.2018.02.001.
  • [6] Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology. 2008; 33(2):320-331. https://doi.org/10.1038/sj.npp.1301410.
  • [7] Perna G, Alciati A, Sangiorgio E, Caldirola D, Nemeroff CB. Personalized Clinical Approaches to Anxiety Disorders. Adv Exp Med Biol. 2020; 1191:489-521. https://doi.org/10.1007/978-981-32-9705-0_25.
  • [8] Tekşen Y, Gündüz MK, Berikten D, Özatik FY, Aydın HE. Peganum harmala L. seed extract attenuates anxiety and depression in rats by reducing neuroinflammation and restoring the BDNF/TrkB signaling pathway and monoamines after exposure to chronic unpredictable mild stress. Metab Brain Dis. 2024; 39(8):1523-1541. https://doi.org/10.1007/s11011-024-01416-6.
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There are 69 citations in total.

Details

Primary Language English
Subjects Clinical Pharmacology and Therapeutics
Journal Section Research Article
Authors

Mehmet Haktan Ozsagır 0009-0006-7255-2375

Elif Beyzanur Polat 0000-0002-3093-3595

Özlem Tuğçe Çilingir Kaya 0000-0002-2591-9174

Aslı Aykaç 0000-0002-4885-5070

Dilek Özbeyli 0000-0002-4141-6913

Project Number TYL-2024-11465
Submission Date May 3, 2025
Acceptance Date May 30, 2025
Publication Date January 11, 2026
Published in Issue Year 2026 Volume: 30 Issue: 1

Cite

APA Ozsagır, M. H., Polat, E. B., Çilingir Kaya, Ö. T., … Aykaç, A. (2026). Effects of metformin in an experimental chronic unpredictable mild stress model. Journal of Research in Pharmacy, 30(1), 171-185. https://doi.org/10.12991/jrespharm.1690442
AMA Ozsagır MH, Polat EB, Çilingir Kaya ÖT, Aykaç A, Özbeyli D. Effects of metformin in an experimental chronic unpredictable mild stress model. J. Res. Pharm. January 2026;30(1):171-185. doi:10.12991/jrespharm.1690442
Chicago Ozsagır, Mehmet Haktan, Elif Beyzanur Polat, Özlem Tuğçe Çilingir Kaya, Aslı Aykaç, and Dilek Özbeyli. “Effects of Metformin in an Experimental Chronic Unpredictable Mild Stress Model”. Journal of Research in Pharmacy 30, no. 1 (January 2026): 171-85. https://doi.org/10.12991/jrespharm.1690442.
EndNote Ozsagır MH, Polat EB, Çilingir Kaya ÖT, Aykaç A, Özbeyli D (January 1, 2026) Effects of metformin in an experimental chronic unpredictable mild stress model. Journal of Research in Pharmacy 30 1 171–185.
IEEE M. H. Ozsagır, E. B. Polat, Ö. T. Çilingir Kaya, A. Aykaç, and D. Özbeyli, “Effects of metformin in an experimental chronic unpredictable mild stress model”, J. Res. Pharm., vol. 30, no. 1, pp. 171–185, 2026, doi: 10.12991/jrespharm.1690442.
ISNAD Ozsagır, Mehmet Haktan et al. “Effects of Metformin in an Experimental Chronic Unpredictable Mild Stress Model”. Journal of Research in Pharmacy 30/1 (January2026), 171-185. https://doi.org/10.12991/jrespharm.1690442.
JAMA Ozsagır MH, Polat EB, Çilingir Kaya ÖT, Aykaç A, Özbeyli D. Effects of metformin in an experimental chronic unpredictable mild stress model. J. Res. Pharm. 2026;30:171–185.
MLA Ozsagır, Mehmet Haktan et al. “Effects of Metformin in an Experimental Chronic Unpredictable Mild Stress Model”. Journal of Research in Pharmacy, vol. 30, no. 1, 2026, pp. 171-85, doi:10.12991/jrespharm.1690442.
Vancouver Ozsagır MH, Polat EB, Çilingir Kaya ÖT, Aykaç A, Özbeyli D. Effects of metformin in an experimental chronic unpredictable mild stress model. J. Res. Pharm. 2026;30(1):171-85.