Farelerde Sirkadiyen Ritim Bozulmasına Bağlı Olarak Oluşan Kardiyak Lezyonlar Üzerine Butafosfan ve Deksapantenolün Koruyucu Etkileri

Abstract

Sirkadiyen ritim bozulması (SRB), kardiyak patolojiyle bağlantılı önemli bir stres faktörüdür, ancak histopatolojik özellikleri ve moleküler tetikleyicileri tam olarak anlaşılamamıştır. Bu çalışma, farelerde SRB'nin indüklediği miyokardiyal lezyonları karakterize etmeyi ve butafosfan (BUT) ile deksapantenolün (DEX) tek başına ve kombinasyon halinde koruyucu etkilerini histopatolojik ve immünohistokimyasal analizlerle değerlendirmeyi amaçlamıştır. Erkek C57BL/6 fareler, 19 gün boyunca düzensiz aydınlık-karanlık döngülerine maruz bırakıldı ve beş gruba ayrıldı: kontrol, SRB, SRB+BUT (200 mg/kg/gün, s.c.), SRB+DEX (1000 mg/kg/gün, i.p.) ve SRB+BUT+DEX. Kalp dokuları histopatolojik değişiklikler ve Bax, Bcl-2 ile TNF- α'nın immünohistokimyasal immünreaktivitesi açısından değerlendirildi. Lezyonlar ve boyanma yarı-kantitatif olarak skorlandı. SRB grubunda, hiperemi, kanama, enflamasyon ve dejenerasyon içeren şiddetli miyokardiyal hasar ile ilişkili olarak, Bax ve TNF-α immünreaktivitesinde artış, Bcl-2 immünreaktivitesinde azalma gözlendi. BUT veya DEX monoterapisi bu değişiklikleri kısmen iyileştirdi. Kombine BUT+DEX tedavisi ise en belirgin iyileşme ile ilişkili bulunmuş, miyokardiyal mimarinin büyük ölçüde korunduğu ve apoptotik ile inflamatuar belirteçlerin immünreaktivite paternlerinde iyileşme gözlendiği belirlenmiştir. Sonuç olarak, butafosfan ve deksapantenolün birlikte uygulanması, farelerde SRB kaynaklı miyokardiyal hasarın azalması ile ilişkili bulunmuş olup, bu etkinin apoptotik ve enflamatuar süreçler üzerinde modülatör bir etki düşündürdüğü değerlendirilmiştir. Bu kombinasyon, sirkadiyen ritim bozulmasıyla ilişkili kardiyak patolojiye karşı potansiyel bir farmakolojik yaklaşım olarak değerlendirilebilir. 

Keywords

• Butafosfan
• dexpanthenol
• histopatoloji
• kalp
• sirkadiyen ritim bozulması

Ethical Statement

Bu çalışma, Burdur Mehmet Akif Ersoy Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu tarafından onaylanmıştır (Onay No: 1464, Tarih: 16.04.2025) ve laboratuvar hayvanlarının bakım ve kullanımıyla ilgili uluslararası kabul görmüş kılavuzlara uygun olarak yürütülmüştür.

Thanks

Yazar, histopatolojik ve immünohistokimyasal değerlendirmelerdeki değerli rehberliği ve uzman desteği için Prof. Dr. Özlem Özmen’e içtenlikle teşekkür eder.

Protective Effects of Butafosfan and Dexpanthenol on Cardiac Lesions Induced by Circadian Rhythm Disruption in Mice

Abstract

Circadian rhythm disruption (CRD) is a significant stressor linked to cardiac pathology, but its histopathological features and molecular drivers are not fully understood. This study aimed to characterize CRD-induced myocardial lesions in mice and evaluate the protective effects of butafosfan (BUT) and dexpanthenol (DEX), alone and combined, using histopathological and immunohistochemical analyses. Male C57BL/6 mice were subjected to irregular light–dark cycles for 19 days and divided into five groups: control, CRD, CRD+BUT (200 mg/kg/day, s.c.), CRD+DEX (1000 mg/kg/day, i.p.), and CRD+BUT+DEX. Cardiac tissues were assessed for histopathological changes and immunohistochemical immunoreactivity of Bax, Bcl-2, and TNF-α. Lesions and staining were scored semi-quantitatively. CRD was associated with severe myocardial damage, including hyperaemia, haemorrhage, inflammation, and degeneration, along with increased Bax and TNF-α immunoreactivity and decreased Bcl-2 immunoreactivity. BUT or DEX monotherapy partially ameliorated these changes. The combined BUT+DEX treatment was associated with the most pronounced improvement, with myocardial architecture appearing largely preserved and an improvement in immunoreactivity patterns of apoptotic and inflammatory markers. In conclusion, combined administration of BUT and DEX was associated with attenuation of CRD-induced myocardial injury in mice more effectively than either agent alone, suggesting a modulatory effect on apoptotic and inflammatory processes. 

Keywords

• Butafosfan
• circadian rhytm disruption
• dexpanthenol
• hearth
• histopathology

Ethical Statement

This study was approved by the Burdur Mehmet Akif Ersoy University Animal Experiments Local Ethics Committee (Approval No: 1464, Date: 16.04.2025) and conducted in accordance with internationally accepted guidelines for the care and use of laboratory animals.

Thanks

The author gratefully acknowledges Prof. Dr. Özlem Özmen for her valuable guidance and expert support in the histopathological and immunohistochemical evaluations.

References

1. Bernardi J, Aromolaran KA, Zhu H, Aromolaran AS. Circadian mechanisms: Cardiac ion channel remodeling and arrhythmias. Front Physiol 2021; 11: 611860.
2. Che Y, Shimizu Y, Hayashi T, Suzuki J, Pu Z, Tsuzuki K, Murohara T. Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock–sGC– cGMP–PKG1 pathway. Sci Rep 2024; 14: 10777.
3. Crnko S, Du Pré BC, Sluijter JP, van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol 2019; 16: 437-47.
4. Doba S, Buzlama A, Kuznetsov A. Pharmacological effects of dexpanthenol. Res J Pharm Technol 2024; 17: 3499-504.
5. Eckle T, Bertazzo J, Khatua TN, Fatemi Tabatabaei SR, Moori Bakhtiari N, Walker LA, Martino TA. Circadian influences on myocardial ischemia-reperfusion injury and heart failure. Circ Res 2024; 134: 675-94.
6. El Jamal N, Lordan R, Teegarden SL, Grosser T, FitzGerald G. The circadian biology of heart failure. Circ Res 2023; 132: 223-37.
7. Erdogan MA, Yigitturk G, Erbas O, Taskıran D. Neuroprotective effects of dexpanthenol on streptozotocin-induced neuronal damage in rats. Drug Chem Toxicol 2022; 45: 2160-8.
8. Fagiani F, Di Marino D, Romagnoli A, Travelli C, Voltan D, Di Cesare Mannelli L, Lanni C. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther 2022; 7: 41.

9. Mattei P, Jacometo CB, Pereira RA, Montagner P, Weiller MAA, dos Santos Teixeira R, Corrêa MN. Pro-inflammatory response markers and neutrophil activity in mice treated with butaphosphan after endotoxin challenge. Res Soc Dev 2022; 11: e72111032386.
10. Mechesso AF, Kim YG, Park SC. Effects of butaphosphan and cyanocobalamin combination on plasma immune and biochemical parameters of olive flounder under crowding stress. Aquac Res 2019; 50: 1611-7.
11. Mohd Azmi NAS, Juliana N, Azmani S, Mohd Effendy N, Abu IF, Mohd Fahmi Teng NI, Das S. Cortisol on circadian rhythm and its effect on the cardiovascular system. Int J Environ Res Public Health 2021; 18: 676.
12. O’Siorain JR, Cox SL, Payet CK, Nally FK, He Y, Drewinski TT, Curtis A. Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages. FASEB J 2024; 38: e70235.
13. Polat S, Ekici O, Coskun EI, Ozhan O, Yildiz A, Vardi N, Erdemli Z, Turkoz Y, Acet A, Parlakpinar H. Dexpanthenol prevents ovarian ischemic damage via antioxidant mechanisms in rats. Med Science 2023; 12(4): 1213-7.
14. Pourcet B, Duez H. Circadian control of inflammasome pathways: Implications for circadian medicine. Front Immunol 2020; 11: 1630.
15. Rabinovich-Nikitin I, Lieberman B, Martino TA, Kirshenbaum LA. Circadian-regulated cell death in cardiovascular diseases. Circulation 2019; 139: 965-80.
16. Tepebaşı MY, Büyükbayram Hİ, Özmen Ö, Taşan Ş, Selçuk E. Dexpanthenol ameliorates doxorubicin-induced lung injury by regulating ER stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol 2023; 396: 1837-48.
17. Tsai LL, Tsai YC, Hwang K, Huang YW, Tzeng JE. Repeated light–dark shifts speed up body weight gain in male F344 rats. Am J Physiol Endocrinol Metab 2005; 289: E212-7.
18. Weiller MAA, Alvarado-Rincón JA, Jacometo CB, Barros CC, de Souza ICC, Hax LT, Corrêa MN. Butaphosphan effects on glucose metabolism involve insulin signalling. Nutrients 2020; 12: 1856.
19. Yildiz A, Demiralp T, Vardi N, Otlu G, Taslidere E, Cirik H, Gurel E. Protective effects of dexpanthenol in carbon tetrachloride-induced myocardial toxicity in rats. Tissue Cell 2022; 77: 10182.