Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture

Köse, Duygu; Köse, Ahmet; Halıcı, Zekai; Gürbüz, Muhammed Ali; Aydın, Ali; Uğan, Rüstem Anıl; Karaman, Adem; Toktay, Erdem

doi:10.1016/j.ejphar.2020.173577

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…Melatonin, produced by the pineal gland, has been shown to be an effective antioxidant, and has in vivo and in vitro activity because of its lipophylic property which can easily enter the nucleus and other organelles (5). Also, in recently years, the in vitro osteoblastic differentiation and bone formation effect has been demonstrated (22)(23)(24). Melatonin at pharmacological doses (30 mg/kg) stimulates osteoblast differentiation and mineralization of matrix and it may regulate osteoclastic activity via superoksid dismutase in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Melatoni̇n Agoni̇sti̇ Olan Ramelteonun Metotreksat Kaynakli Kemi̇k Toksi̇si̇tesi̇ne Karşi Koruyucu Etki̇si̇

Dinçer¹

2022

SDÜ Tıp Fakültesi Dergisi

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AmaçMetotreksat (MTX) büyüme durması ve kemik mineral yoğunluğunun azalması dahil olmak üzere kemik morbiditesine neden olan anti-metabolittir. Epifiz bezi tarafından üretilen melatonin, insan kemik hücrelerinde de birçok olumlu etkiye ve kemik üzerinde olumlu etkilere sahiptir. Ramelteon (RMT), seçici olmayan bir melatonin reseptör agonistidir. Bu çalışmada, bir melatonin agonisti olan ramelteonun MTX kaynaklı kemik toksisitesi üzerinde koruyucu bir etkisinin olup olmadığını araştırdık. Gereç ve YöntemSıçanlar Grup 1 kontrol grubu olmak üzere 4 gruba ayrıldı; Grup 2 MTX grubu (20 mg/kg); Grup 3 MTX+R-MT (20 mg/kg + 10 mg/kg); Grup 4 RMT (10 mg/kg). Ratlara gruplara göre ikinci gün oral ramelteon ve intraperitoneal mtx uygulandı. 7 gün sonra uzun kemikler hematoksilen-eozin (HE) boyama ile histolojik olarak ve Catepsin K ve RUN X2 boyama ile immüno-histokimyasal olarak değerlendirildi. İstatistiksel analiz için grupların immünhistokimyasal skorları gruplar arasında karşılaştırıldı, bu amaçla SPSS-22.00 paket programı ile Oneway ANOVA Duncan testi kullanıldı. BulgularKemik doku kesitlerinin H&E boyamasında kontrol grubu (grup I) ile deney grupları (grup II-grup III-grup IV) arasında anlamlı bir fark yoktu (p>0.05). CAT-K ve RUN-X immün boyamasında grupların hiçbirinde pozitif boyanma gözlenmedi (p>0.05). SonuçRamelteonun, sağlam kemik dokusu üzerinde yüksek doz metotreksatın neden olduğu kemik toksisitesinde, kemik döngüsünde, histopatolojik ve immünohistokimyasal olarak anabolik bir işlevi olmadığı gösterilmiştir.

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Section: Discussionmentioning

confidence: 99%

“…Ramelteon (RMT) is non-selective peripheral melatonin receptor (MT) agonist too. Kose D. et al has showed their application of RMT 3 mg/kg resulted in bone healing with increased new knitting bone tissue but in different RMT doses they reported that there was no difference between 6 mg/kg RMT dose and 3 mg/kg RMT dose on bone union (24).…”

Section: Discussionmentioning

confidence: 99%

Melatoni̇n Agoni̇sti̇ Olan Ramelteonun Metotreksat Kaynakli Kemi̇k Toksi̇si̇tesi̇ne Karşi Koruyucu Etki̇si̇

Dinçer¹

2022

SDÜ Tıp Fakültesi Dergisi

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“…Conversely, agomelatine, as an MT-1 and MT-2 agonist, has not been studied in osteoporosis occurring among menopausal women. However, one recent study showed that agomelatine has ameliorative effects on bone fracture healing in rodents ( 54 ). Bone mass is known to be formed by either excessive osteoclastic bone resorption or reduced osteoblastic bone formation.…”

Section: Agomelatine and Melatonin In Depression Insomnia And Bone Activitymentioning

confidence: 99%

Agomelatine, A Potential Multi-Target Treatment Alternative for Insomnia, Depression, and Osteoporosis in Postmenopausal Women: A Hypothetical Model

2021

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Insomnia, which is associated with menopausal depression, is a common symptom of menopause. Both symptoms have a common etiology, and can affect each other significantly. Pharmacological interventions, including hypnotics and antidepressants, and non-pharmacological therapies are generally administered in clinical practice for insomnia treatment. As another menopausal disorder, osteoporosis is described as a disease of low bone mineral density (BMD), affecting nearly 200 million women worldwide. Postmenopausal osteoporosis is common among middle-aged women. Since postmenopausal osteoporosis mainly results from low estrogen levels, menopausal hormone therapy (HT) is considered the first-line option for the prevention of osteoporosis during the menopausal period. However, almost no study has evaluated novel treatments for the combined prevention of insomnia, depression, and osteoporosis. Hence, it is necessary to develop new multi-target strategies for the treatment of these disorders to improve the quality of life during this vulnerable period. Melatonin is the major regulator of sleep, and it has been suggested to be safe and effective for bone loss therapy by MT-2 receptor activity. As a result, we hypothesize that agomelatine, an MT-1 and MT-2 receptor agonist and 5-HT2C receptor antagonist, holds promise in the combined treatment of insomnia, depression, and osteoporosis in middle-aged women during menopause.

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“…Recent studies have also implied that melatonin can also influence bone metabolism by inhibiting osteoclastogenesis and promoting osteogenic differentiation 7,8 . Melatonin has been found promising therapeutic prospects of bone regenerating 9,10 . Some randomized controlled clinical trials demonstrated that melatonin treatment was associated with reduction in periodontal inflammation and can significantly improve clinical periodontal parameters, such as probing depth and clinical attachment loss 11,12 .…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Melatonin has been found promising therapeutic prospects of bone regenerating. 9,10 Some randomized controlled clinical trials demonstrated that melatonin treatment was associated with reduction in periodontal inflammation and can significantly improve clinical periodontal parameters, such as probing depth and clinical attachment loss. 11,12 However, some studies found that melatonin could suppress both osteoblasts and osteoclasts, 13 and physiological levels of melatonin can suppress osteogenesis of osteogenic differentiation of hPDLSCs by inhibiting mitochondrial functions.…”

Section: Introductionmentioning

confidence: 99%

Melatonin promoted osteogenesis of human periodontal ligament cells by regulating mitochondrial functions through the translocase of the outer mitochondrial membrane 20

Sun

Zheng

Liu

et al. 2022

J of Periodontal Research

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Background and Objective: Melatonin plays an important role in various beneficial functions, including promoting differentiation. However, effects on osteogenic differentiation, especially in human periodontal cells (hPDLCs), still remain inconclusive.Mitochondria are highly dynamic organelles that play an important role in various biological processes in cells, including energy metabolism and oxidative stress reaction. Furthermore, the translocase of the outer mitochondrial membrane 20 (TOM20) is responsible for recognizing and transporting precursor proteins. Thus, the objective of this study was to evaluate the functionality of melatonin on osteogenesis in human periodontal cells and to explore the involved mechanism of mitochondria.

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Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture

Cited by 9 publications

References 23 publications

Melatoni̇n Agoni̇sti̇ Olan Ramelteonun Metotreksat Kaynakli Kemi̇k Toksi̇si̇tesi̇ne Karşi Koruyucu Etki̇si̇

Melatoni̇n Agoni̇sti̇ Olan Ramelteonun Metotreksat Kaynakli Kemi̇k Toksi̇si̇tesi̇ne Karşi Koruyucu Etki̇si̇

Agomelatine, A Potential Multi-Target Treatment Alternative for Insomnia, Depression, and Osteoporosis in Postmenopausal Women: A Hypothetical Model

Melatonin promoted osteogenesis of human periodontal ligament cells by regulating mitochondrial functions through the translocase of the outer mitochondrial membrane 20

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