Background & Aims

Osteoarthritis (OA) is a highly prevalent chronic rheumatic disease, characterized by cartilage loss with consequent joint pain and dysfunction (most commonly of the knees) [1]. Even though it is primarily a joint disorder, OA can have substantial extra-articular complications, including increased risk of cognitive decline [2]. Despite its high prevalence, currently no drug has been approved as a disease-modifying therapy, and most available treatment options only alleviate joint pain [1,3]. In recent years, metformin (a well-known antidiabetic drug) has been shown to be effective in relieving pain and preventing cartilage loss in OA in preclinical and human studies [3]. Here we aimed to expand the existing data on the effects of metformin in OA, and examine its effects on pain-related behavior, extra-articular manifestations (cognitive performance) and level of joint oxidative damage in a model of OA.

Methods

OA was induced in male and female Wistar rats with an intraarticular injection of sodium monoiodoacetate (MIA; 2 mg). Saline-control rats received an intraarticular injection of saline [4]. Following induction, rats received metformin daily (100 mg/kg¸ orally) for 28 days. During this period, different tests were used to assess pain-related behavior and cognitive performance. Pain-related behavior was examined using the weight-bearing and Von Frey tests (assessment of weight-bearing asymmetry and mechanical hypersensitivity, respectively). The novel object recognition test (NORT) was used to assess cognitive performance. After the 28-day period, rats were sacrificed and knee tissue was collected for determination of oxidative stress parameters: superoxide anion radicals (O2•-), total pro-oxidant status (TOS), advanced oxidation protein products (AOPP) and malondialdehyde (MDA). Results were analyzed with one-way ANOVA or two-way repeated measures ANOVA (with Tukey post-hoc test).

Results

Intraarticular MIA produced significant weight-bearing asymmetry and mechanical hypersensitivity in rats of both sexes (P < 0.001 vs saline-controls). Metformin treatment reduced weight bearing asymmetry and mechanical hypersensitivity in male and female rats (P ? 0.008 vs MIA-controls). In NORT, OA induction impaired cognitive performance, i.e. discrimination indexes of male and female MIA-controls were significantly lower compared to saline-controls (P ? 0.002). Metformin reversed OA-induced cognitive deficits in NORT, and significantly increased discrimination indexes in rats of both sexes (P ? 0.033 vs MIA-controls). Lastly, all parameters of knee oxidative damage were significantly increased in male and female rats with OA (P ? 0.049 vs saline-controls). Metformin significantly reduced O2•-, TOS, AOPP and MDA levels in male rats (P ? 0.041 vs MIA-controls), whereas in female rats it significantly reduced TOS, AOPP and MDA (P ? 0.009 vs MIA-controls), but not O2•-.

Conclusions

Prolonged metformin treatment produced several beneficial effects in male and female rats with OA. Metformin was capable of alleviating pain-related behavior (weight-bearing asymmetry and mechanical hypersensitivity). Furthermore, metformin was effective in reversing cognitive impairment of rats with OA, which indicates its potential utility in relieving extra-articular complications of OA. Lastly, metformin reduced the level of oxidative damage of knee tissue in rats with OA. These findings suggest that anti-oxidative effects could be an additional mechanism contributing to metformin’s disease-modifying properties.

References

1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet 2019;393:1745-59. doi: 10.1016/S0140-6736(19)30417-9.
2. Weber A, Mak SH, Berenbaum F, et al. Association between osteoarthritis and increased risk of dementia: A systemic review and meta-analysis. Medicine (Baltimore) 2019;98:e14355. doi: 10.1097/MD.0000000000014355.
3. Lim YZ, Wang Y, Estee M, et al. Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Osteoarthritis Cartilage. 2022;30(11):1434-42. doi: 10.1016/j.joca.2022.05.005.
4. Nasti? K, Pecikoza U, Labudovi?-Borovi? M, et al. The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis. Biomed Pharmacother. 2023;166:115360. doi: 10.1016/j.biopha.2023.115360.

Presenting Author

Uroš Pecikoza

Poster Authors

Uroš Pecikoza, M. Pharm, PhD

MPharm, PhD

Department of Pharmacology, Faculty of Pharmacy, University of Belgrade

Lead Author

E-mail

Katarina Nastic

Faculty of Pharmacy, University of Belgrade

Lead Author

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Jelena Kotur-Stevuljevi? (degrees: MPharm

PhD)

University of Belgrade - Faculty of Pharmacy (Department of Medical Biochemistry)

Lead Author

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Ana Micov (degrees: MPharm

PhD)

University of Belgrade – Faculty of Pharmacy (Department of Pharmacology)

Lead Author

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Aleksandar Jovanovi? (degrees: MD

PhD)

University of Nicosia – Medical School (Department of Basic and Clinical Sciences)

Lead Author

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Maja Tomi? (degrees: MPharm

PhD)

University of Belgrade – Faculty of Pharmacy (Department of Pharmacology)

Lead Author

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Radica Stepanovi?-Petrovi? (degrees: MPharm

PhD)

University of Belgrade – Faculty of Pharmacy (Department of Pharmacology)

Lead Author

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Topics

  • Models: Musculoskeletal

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