The Effects of Melatonin on Angiogenesis and Wound Healing

Purpose The pineal gland hormone melatonin is a well-known neoroendocrine hormone. In addition to its immunomodulator effect, it also has a positive effect on monocyte, cytokine, and fibroblast proliferations, which also influence angiogenesis. This study investigated the effects of melatonin hormone on angiogenesis in wound healing on 100 Wistar-Albino rats.Methods The rats were divided into two groups. Melatonin dissolved in 0.9% NaCl was administered to the study group in a dose of 0.4mg/kg/rat per day (0.25cc/rat per day), and 0.9% NaCl to the control group in a dose of 0.25cc/rat per day. Incisions 5cm in length were made on the back skin of the rats and the wounds were closed with a skin stapler. Excisional biopsies from healing tissues were taken on the 3rd, 7th, 10th, 14th, and 21st postoperative days. Angiogenesis was evaluated in healing tissues by light and electron microscopy and by hydroxyproline level measurements.Results The commencement of neovascularization and a significant increase (P 0.05) in the number of vessels were observed at all stages of the study group but not in the control group. The tissue hydroxyproline levels were also higher in the study group than in the control group.Conclusions Melatonin may have a positive effect on both angiogenesis and wound healing.The preliminary results of this study have been published in the Turkish Journal of Surgery     

Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands

RATIONALE: Pineal and Harderian gland melatonin production as well as plasma melatonin levels were investigated in male Wistar rats (12 weeks old) after administration of diazepam, a benzodiazepine widely used as anxiolytic. OBJECTIVE: The present study investigates the effects of a chronic administration of diazepam on pineal and Harderian gland melatonin contents. METHODS: Diazepam was administered subcutaneously, for 21 days, at a dosage of 3 mg/kg body weight per day, 1 h before the onset of darkness. RESULTS: Diazepam clearly affected pineal melatonin biosynthesis and plasma melatonin levels. Diazepam reduced the pineal melatonin content (by a factor of 2) and the activity of N-acetyltransferase (NAT) (by a factor of 3.5), as well as plasma melatonin levels (by a factor of 1.5), but had no effects on pineal hydroxyindole-O-methyltransferase activity. By contrast to the pineal gland, diazepam failed to affect the Harderian gland melatonin content. CONCLUSIONS: Our results suggest that the inhibition of melatonin production induced by diazepam in vivo may be due to a direct action of this benzodiazepine on the pineal gland, through its action on NAT, the key enzyme of melatonin synthesis, and that the control of melatonin production in the Harderian glands may be different from that observed in the pineal gland.     

N—（N—乙酰基—L—氨基酰基）—5—甲氧基色胺的镇痛活性和抗肿瘤活性

在褪黑激素的结构修饰中引入L－氨基酸形成N－（N－乙酰基－L－氨基酰基）－5－甲氧基色胺,这些化合物分别用小鼠甩尾法和人皮肤黑色素瘤细胞评价了镇痛活性和抗肿瘤活性,结果显示部分化合物的活性优于褪黑激素。     

Effect of melatonin on the functional recovery from experimental traumatic compression of the spinal cord

Spinal cord injury is an extremely severe condition with no available effective therapies. We examined the effect of melatonin on traumatic compression of the spinal cord. Sixty male adult Wistar rats were divided into three groups: sham-operated animals and animals with 35 and 50% spinal cord compression with a polycarbonate rod spacer. Each group was divided into two subgroups, each receiving an injection of vehicle or melatonin (2.5 mg/kg, intraperitoneal) 5 min prior to and 1, 2, 3, and 4 h after injury. Functional recovery was monitored weekly by the open-field test, the Basso, Beattie and Bresnahan locomotor scale and the inclined plane test. Histological changes of the spinal cord were examined 35 days after injury. Motor scores were progressively lower as spacer size increased according to the motor scale and inclined plane test evaluation at all times of assessment. The results of the two tests were correlated. The open-field test presented similar results with a less pronounced difference between the 35 and 50% compression groups. The injured groups presented functional recovery that was more evident in the first and second weeks. Animals receiving melatonin treatment presented more pronounced functional recovery than vehicle-treated animals as measured by the motor scale or inclined plane. NADPH-d histochemistry revealed integrity of the spinal cord thoracic segment in sham-operated animals and confirmed the severity of the lesion after spinal cord narrowing. The results obtained after experimental compression of the spinal cord support the hypothesis that melatonin may be considered for use in clinical practice because of its protective effect on the secondary wave of neuronal death following the primary wave after spinal cord injury.     

Melatonin and human reproduction: Shedding light on the darkness hormone

Melatonin, N-acetyl-5-methoxytryptamine, is a molecule with diverse physiological functions. This neuro-hormone affects reproductive performance in a wide variety of species. In most animals, but not exclusively all, melatonin has an antigonadotrophic effect. The seasonal changes in the number of hours per day that melatonin is secreted mediate the temporal coupling of reproductive activity to seasonal changes in day-length. These observations stimulated a search for a role for the pineal gland and melatonin in human reproduction. Clinical experience related to this issue has yielded inconclusive and sometimes conflicting results. This article reviews the current available evidence concerning the effects of melatonin on human reproductive processes (e.g., puberty, ovulation, pregnancy, and fertility). Possible reasons for the vagueness and elusiveness of the clinical effects are discussed.     

Cysteamine effects on somatostatin, catecholamines, pineal NAT and melatonin in rats

The thiol reagent cysteamine was administered to adult male rats with the aim of investigating its effect on different neural and pineal components. As expected, immunoreactive somatostatin decreased in the median eminence (ME) (p less than 0.05) and gastric antrum (p less than 0.05) after cysteamine; however, no significant change was observed in the pineal IRS content after drug treatment. A decrease in norepinephrine was observed in the ME (p less than 0.001), hypothalamus (p less than 0.001) and pineal gland (p less than 0.05), together with a rise in ME (p less than 0.005) and hypothalamic dopamine (p less than 0.005) content; these results are consistent with a dopamine-beta-hydroxylase inhibiting effect of cysteamine. No effect was observed on hypothalamic serotonin and 5-hydroxyindole-acetic acid content. Pineal N-acetyltransferase (NAT) activity was significantly higher (p less than 0.05) after cysteamine than after saline, but no statistically significant effect was observed on pineal melatonin content. The mechanism involved in the NAT rise is presumably not related to the known stimulatory effect of norepinephrine, which fell after cysteamine. It is suggested that cysteamine may act at an intracellular level, inhibiting NAT degradation, an effect demonstrated in vitro and thought to be related to a thiol:disulfide exchange mechanism.     

The effect of stress on melatonin and serotonin in rat brain

The effect of immobilization, cold and immobilization plus cold stress on rat pineal indoles and brain serotonin (5-HT) has been studied. Only combined immobilization and cold stress resulted in an increase of pineal melatonin and N-acetylserotonin (NAS). Furthermore, the ratio of 5-hydroxyindole acetic acid (5-HIAA) to 5-HT was significantly decreased in rats subjected to the combined stress. This effect was evident in the pineal as well as the hypothalamus and brainstem. Although showing no effect on melatonin, NAS, or the 5-HIAA/5-HT ratio, immobilization alone produced a significant increase in pineal 5-HT concentration. This 5-HT increase was also evident in the hypothalamus and brainstem. Synaptosomal 5-HT uptake was examined as a functional test of 5-HT activity, but was unchanged by the combined stress. Although cold alone did not significantly affect serum corticosterone levels, it did augment the corticosterone increase induced by immobilization. These results are discussed in the context of previous investigations of the endogenous monoamine oxidase inhibitor, tribulin.     

Does circadian rhythm disruption induced by light-at-night has beneficial effect of melatonin on sciatic nerve injury?

Melatonin stimulates peripheral nerve regeneration. However, the precise effect of Melatonin on nerve repair in dark period have not been clarified. The aim of the present study was to investigate the effect of melatonin on sciatic nerve injury after melatonin was given to rats in the morning or evening by means of combined analysis. This is the first study to investigate the influence of melatonin on sciatic nerve in cut injury two different times of the day. 60 adult female Wistar rats were divided into 4 groups: control (Group 1), sham-operated (Group 2), sciatic nerve cut + melatonin treatment in light (Group 3), sciatic nerve cut + melatonin treatment in dark (Group 4). Melatonin was administered intraperitoneally at dose of 50 mg/kg/day for six weeks. Recovery of function was analyzed by structural (biochemical properties of the antioxidant levels and ultrastructural analysis) and functional analyses (Sciatic function index, pinch test). The data demonstrated beneficial effect of melatonin in light period. However significant beneficial effect of melatonin was detected on the recovery of the cut sciatic nerve in dark period. Melatonin treatment was unable to influence on the recovery of the cut sciatic nerve in dark period. This means that the effect of melatonin the recovery of the cut injured sciatic nerve depends on the time of treatment may be attributed to its circadian rhythm.     

Melatonin-loaded lecithin/chitosan nanoparticles: Physicochemical characterisation and permeability through Caco-2 cell monolayers

In this study, the potential of lecithin/chitosan nanoparticles (NPs) as a mucoadhesive colloidal nanosystem for transmucosal delivery of melatonin was investigated. The size, zeta potential and melatonin loading of the lecithin/chitosan NPs were investigated as a function of lecithin type (Lipoid S45, S75 and S100) and chitosan content in the preparation. The NPs were characterised by mean diameter and zeta potential ranging between 121.6 and 347.5 nm, and 7.5 and 32.7 mV, respectively, and increasing with lecithin-negative charge and chitosan content in the preparation. Melatonin loadings were up to 7.1%. All NPs were characterised by prolonged release profiles with an initial burst (approximately 25%), followed by a slow release phase. Approximately 60–70% of melatonin was released in 4 h. The permeability of melatonin was investigated using Caco-2 cells as an in vitro model of the epithelial barrier. Melatonin permeability from an NP suspension prepared with Lipoid S45 lecithin and a lecithin-to-chitosan weight ratio (L/C) of 20:1 (sample C2) was significantly improved compared to the permeability of melatonin from the solution (P < 0.001) and from all other NPs investigated (P < 0.05). The results obtained by the cell viability studies (MTT and LDH leakage assays) showed that C2 NP suspension did not induce plasma membrane damage or decrease cell viability and could be safely applied to Caco-2 cells in the concentration range tested (<400 μg/ml).