DENEYSEL DİYABETİN NEDEN OLDUĞU DEPRESYON TEDAVİSİNDE MİNOSİKLİN VE MİNOSİKLİN+METFORMİN KULLANIMI

Year 2022, , 432 - 443, 29.05.2022

Merve İnci Çamçi , Meral Erdinç , Emre Uyar , İlker Kelle

https://doi.org/10.33483/jfpau.1098642

Abstract

Amaç: Minosiklin, santral sinir sistemine geçebilen, ikinci kuşak tetrasiklin grubu bir antibiyotiktir. Minosiklinin anti-inflamatuar, mikroglial aktivasyonu azaltma, anti-apoptotik, antioksidan özellikleri olduğu bilinmektedir. Son yıllarda diyabet ve depresyon arasında çift yönlü bir ilişki olduğunun ve fizyopatolojilerinde ortak yolaklardan birinin inflamasyon olduğunun ileri sürülmesi ile minosiklinin depresyon üzerine etkileri çalışılmaya başlanmıştır. Bu çalışmada minosiklinin tek başına ve diyabet tedavisinde kullanılan metformin ile kombinasyonu şeklinde kullanımının, diyabet ile ilişkili depresyon üzerine etkilerinin ortaya konması amaçlandı.

Gereç ve Yöntem: Farelerde insandakine benzer tip 2 diyabet modeli oluşturmak için 4 haftalık yüksek kalorili diyetin ardından ardışık beş gün, günde 1 defa streptozotosin (50mg/kg) uygulandı, uygulamadan 1 hafta sonra açlık kan glukoz düzeyi 200 mg/dl’nin üzerinde olan deneklerde diyabetin oluştuğu kabul edilip deneye dahil edildi. Streptozotosin (STZ) enjeksiyonundan iki hafta sonra minosiklin (40mg/kg), fluoksetin (20mg/kg) ve metformin (200mg/kg) 7 gün süre ile günde bir defa uyguladı. İlaç uygulamaları tamamlandıktan sonra; lokomotor aktivitenin belirlenmesi için açık alan testi, depresyon düzeyinin belirlenmesi için zorunlu yüzme testi yapıldı.

Sonuç ve Tartışma: Diyabetin ve uygulanan ilaçların lokomotor aktivitede anlamlı bir değişiklik oluşturmadığı, minosiklin ve minosiklin-metformin kombinasyonunun ise depresyon tedavisinde en az fluoksetin kadar etkili olduğu sonucuna varıldı. Antidepresan etkinin kısa sürede başlamasının hastanın tedaviye uyuncu ve diyabetin prognozu açısından oldukça önemli olduğu bilinmektedir. Bu nedenle de minosiklin uygulamasının gösterdiği antidepresan etki üzerine yapılan çalışmalar derinleştirilmeli, etkinin mekanizması araştırılmalıdır.

Keywords

Depresyon, diyabet, minosiklin

Supporting Institution

Dicle Üniversitesi Bilimsel Araştırma Projeleri komisyonu

Project Number

TIP.21.012

EFFECT OF MINOCYCLINE AND MINOSCYCLINE+METFORMIN ON EXPERIMENTAL DIABETES-RELATED DEPRESSION

Abstract

Objective: Minocycline is a second-generation tetracycline group antibiotic that acts on the central nervous system. Minocycline reduces microglial activation and has anti-inflammatory, anti-apoptotic, and antioxidant properties. Recently, it has been proposed that there is a bidirectional relationship between diabetes and depression and that inflammation is one of the common pathways in their pathophysiology. The effects of minocycline on depression were then investigated. This study aimed to reveal the effects of minocycline alone or in combination with metformin, which is used in the treatment of diabetes, on diabetes-related depression.

Material and Method: For this purpose, to establish a human-like type 2 diabetes model in mice, streptozotocin (STZ) (50mg/kg) was administered once a day for five consecutive days after a 4-week high-fat diet. Animals with blood glucose levels ≥200 mg/dl were considered diabetic and employed in this experiment. Minocycline (40 mg/kg), fluoxetine (20 mg/kg), and metformin (200 mg/kg) were given once a day for 7 days two weeks after STZ injection. After the drug injections were completed, an open field test was used to determine locomotor activity and a forced swimming test was used to determine depression level.

Result and Discussion: It was concluded that diabetes and the drugs administered did not induce a significant change in locomotor activity, and that the minocycline and minocycline-metformin combination was at least as effective as fluoxetine in treating depression. It is recognized that the initiation of antidepressant effects in a short period is critical for patient adherence to therapy and diabetes prognosis. In conclusion, antidepressant-like effects of subchronic minocycline treatment appear to be potent as classical antidepressants. The mechanisms underlying minocycline's effects on mood should be broadly investigated to increase our understanding of depression and unveil potential novel therapies in depression management.

Keywords

Depression, diabetes, minocycline

Project Number

TIP.21.012

References

• 1. Alam, U., Asghar, O., Azmi, S., & Malik, R. A. (2014). General aspects of diabetes mellitus. Handb Clin Neurol, 126, 211-222. [CrossRef]
• 2. Vancampfort, D., Correll, C. U., Galling, B., Probst, M., De Hert, M., Ward, P. B., . . . Stubbs, B. (2016). Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry, 15(2), 166-174. [CrossRef]
• 3. Buchberger, B., Huppertz, H., Krabbe, L., Lux, B., Mattivi, J. T., & Siafarikas, A. (2016). Symptoms of depression and anxiety in youth with type 1 diabetes: A systematic review and meta-analysis. Psychoneuroendocrinology, 70, 70-84. [CrossRef]
• 4. Holt, R. I., de Groot, M., & Golden, S. H. (2014). Diabetes and depression. Curr Diab Rep, 14(6), 491. [CrossRef]
• 5. Rosenblat, J. D., & McIntyre, R. S. (2018). Efficacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials. Journal of Affective Disorders, 227, 219-225. [CrossRef]
• 6. Tumminia, A., Vinciguerra, F., Parisi, M., & Frittitta, L. (2018). Type 2 Diabetes Mellitus and Alzheimer's Disease: Role of Insulin Signalling and Therapeutic Implications. Int J Mol Sci, 19(11). [CrossRef]
• 7. Alzoubi, A., Abunaser, R., Khassawneh, A., Alfaqih, M., Khasawneh, A., & Abdo, N. (2018). The Bidirectional Relationship between Diabetes and Depression: A Literature Review. Korean J Fam Med, 39(3), 137-146. [CrossRef]
• 8. Nouwen, A., Winkley, K., Twisk, J., Lloyd, C. E., Peyrot, M., Ismail, K., . . . European Depression in Diabetes Research, C. (2010). Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia, 53(12), 2480-2486. [CrossRef]
• 9. Zhou, X., Gan, T., Fang, G., Wang, S., Mao, Y., & Ying, C. (2018). Zeaxanthin improved diabetes-induced anxiety and depression through inhibiting inflammation in hippocampus. Metab Brain Dis, 33(3), 705-711. [CrossRef]
• 10. da Silva Dias, I. C., Carabelli, B., Ishii, D. K., de Morais, H., de Carvalho, M. C., Rizzo de Souza, L. E., . . . Zanoveli, J. M. (2016). Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes. Mol Neurobiol, 53(10), 6997-7009. [CrossRef]
• 11. Zhu, X., Zhang, Y. M., Zhang, M. Y., Chen, Y. J., & Liu, Y. W. (2021). Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway. Metab Brain Dis, 36(7), 1969-1983. [CrossRef]
• 12. Sakurai, M., Iwasa, R., Sakai, Y., & Morimoto, M. (2021). Minocycline prevents depression-like behavior in streptozotocin-induced diabetic mice. Neuropathology, 41(2), 109-117. [CrossRef]
• 13. Zhang, C., Deng, J., Liu, D., Tuo, X., Xiao, L., Lai, B., . . . Wang, N. (2018). Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARalpha/PPARgamma coactivator-1alpha pathway. Br J Pharmacol, 175(22), 4218-4228. [CrossRef]
• 14. Path, G., Mehana, A. E., Pilz, I. H., Alt, M., Baumann, J., Sommerer, I., . . . Seufert, J. (2020). NUPR1 preserves insulin secretion of pancreatic beta-cells during inflammatory stress by multiple low-dose streptozotocin and high-fat diet. Am J Physiol Endocrinol Metab, 319(2), E338-E344. [CrossRef]
• 15. Cheng, Y., Yu, X., Zhang, J., Chang, Y., Xue, M., Li, X., . . . Chen, L. (2019). Pancreatic kallikrein protects against diabetic retinopathy in KK Cg-A(y)/J and high-fat diet/streptozotocin-induced mouse models of type 2 diabetes. Diabetologia, 62(6), 1074-1086. [CrossRef]
• 16. Kazmi, S. A. R., Qureshi, M. Z., Sadia, Alhewairini, S. S., Ali, S., Khurshid, S., . . . Mughal, T. A. (2021). Minocycline-Derived Silver Nanoparticles for Assessment of Their Antidiabetic Potential against Alloxan-Induced Diabetic Mice. Pharmaceutics, 13(10). [CrossRef]
• 17. Camargos, Q. M., Silva, B. C., Silva, D. G., Toscano, E. C. B., Oliveira, B. D. S., Bellozi, P. M. Q., . . . Rachid, M. A. (2020). Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke. Brain Res Bull, 155, 1-10. [CrossRef]
• 18. Amorim, D., Puga, S., Braganca, R., Braga, A., Pertovaara, A., Almeida, A., & Pinto-Ribeiro, F. (2017). Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat. Behav Brain Res, 327, 1-10. [CrossRef]