Melatonin Injections Research Articles

The effect of intracerebroventricular injection of melatonin on the period of acquisition, expression, extinction, and reinstatement of morphine conditioned place preference in the male rat: A behavioral and biochemical study.

Behavior in both humans and animals is significantly influenced by the brain's reward system. Many studies have shown that this dopaminergic system is the root of drug addiction and abuse. Melatonin, an indoleamine neurohormone, has been studied for its potential negative effects on addictive drugs such as morphine. This study evaluates the effect of intraventricular melatonin injection during different phases of morphine conditioning. Rats were conditioned with morphine [5 mg/kg; subcutaneously (SC)] for three days. The changes in conditioned place preference (CPP) scores following the injection of different doses of melatonin [25, 50, and 100 μg/kg; intracerebroventricular (ICV)] were investigated during the acquisition, expression, extinction, and reinstatement phases of morphine conditioning. After completing these steps, the c-Fos level in the nucleus accumbens (NAc) was measured using the ELISA technique. The results indicated that daily injections of 50 and 100 μg/kg melatonin during the acquisition and expression phases caused a dose-dependent decrease in the conditioning score. During the extinction phase, melatonin administration reduced its duration incrementally. Notably, only the 100 μg/kg dose significantly decreased morphine reinstatement. In terms of c-Fos levels, which were elevated after morphine consumption, melatonin administration led to a significant reduction across all phases. This study demonstrates the neural interaction between melatonin and the opioid system. The evidence suggests that melatonin may be effective at decreasing drug-related rewards and has potential utility in preventing addiction.

Non-motor behavioral disorders and the structure of hippocampal neurons in experimental parkinsonism and after administration of human umbilical cord-derived multipotent mesenchymal stromal cells and melatonin

Background. The neuroprotective effect of human umbilical cord-derived multipotent mesenchymal stromal cells (hUC-MMSCs) in Parkinson’s disease can depend on the genotype of the recipient and change under the influence of biologically active factors. The purpose was to investigate the effects of transplantation of the hUC-MMSCs as well as their combination with melatonin on indicators of non-motor activity and the structure of hippocampal neurons in mice with an experimental model of parkinsonism, which differ by the H-2 genotype (analogue of human leukocyte antigen). Materials and methods. Adult FVB/N (genotype H-2q) and 129/Sv (genotype H-2b) male mice have received one injection of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin at a dose of 30 mg/kg. Seven days after, the hUC-MMSCs were injected into the tail vein at a dose of 500,000, and from the next day — intraperitoneal melatonin (Sigma, USA) at a dose of 1 mg/kg daily, the course of 14 injections, at 6 p.m. We have evaluated the indicators of non-motor behavior in open field tests (emotional and orientation-exploratory activity), the development of the conditioned reaction of passive avoidance (cognitive function) and the structure of hippocampal neurons. Results. In mice of both strains under the influence of MPTP, the orientation-exploratory and cognitive activities have been suppressed, the emotional activity has been increased and the structure of neurons in the CA1 region and the dentate gyrus has been disturbed. Transplantation of hUC-MMSCs has improved the indicators of orientation-exploratory and cognitive functions in FVB/N mice and the emotional activity in 129/Sv mice. An activating effect of cells on some indicators of emotional behavior (the number of acts of grooming) in mice of both strains has been revealed. The number of pathologically changed neurons in the CA1 region and dentate gyrus in mice of both strains has decreased after transplantation of hUC-MMSCs. Injections of melatonin after the administration of cells have led to the strengthening of their positive effect on the cognitive function in FVB/N mice and on the emotional activity in 129/Sv mice and have also neutralized their negative effects on the number of acts of grooming in mice of both strains. In the hippocampus of such mice, there was a marked restoration of the cytoarchitectonics and morphometric indicators. At the same time, the positive effect of a combination of hUC-MMSCs and melatonin has been more pronounced in 129/Sv mice. Conclusions. Manifestations of the influence of transplanted hUC-MMSCs and their combination with melatonin on the functional state of the nervous system and the structure of hippocampal neurons of mice with a model of parkinsonism largely depend on their H-2 genotype. The results can be the basis for the development of personalized cell therapy for this pathology using hUC-MMSCs.

EFFECT OF MELATONIN ON PLASMA PYRUVATE LEVELS IN ALLOXAN-INDUCED DIABETIC RATS UNDER DIFFERENT PHOTOPERIODS

Some studies suggest that melatonin exerts a stimulating effect by reducing lactate dehydrogenase activity and shifting the balance of redox enzymes towards the predominance of the Krebs cycle, thereby favoring aerobic processes that are more efficient for cellular energy production. Therefore, an in-depth investigation of this effect of melatonin is warranted. The aim of this experimental study was to examine the impact of melatonin on the levels of pyruvic acid in the plasma of rats under physiological conditions and in alloxan-induced diabetes, with a focus on hypo- and hyperfunction of the pineal gland. Methods. The study was conducted on 50 sexually mature male outbred white rats weighing 0.18–0.20 kg. Photoperiodic changes were simulated over a one-week period, with the following conditions: 1) natural light/dark cycle from March 19 to 25, 2024, averaging 12:12 hours; 2) artificial 12:12 light/dark cycle (light from 8:00 a.m. to 8:00 p.m., with illumination at 500 lux); 3) constant light (500 lux) for 24 hours; 4) constant darkness for 24 hours. Alloxan diabetes was induced by intraperitoneal injection of a 5% alloxan monohydrate solution at a dose of 170 mg/kg. Fasting glucose levels were measured using the One Touch Ultra Easy device (Johnson & Johnson, USA). The rats were divided into four groups based on lighting conditions: 1) intact rats; 2) a control group, receiving daily intraperitoneal melatonin injections (10 mg/kg) at 8 a.m. for one week (Sigma, USA); 3) rats with diabetes mellitus; 4) rats with diabetes mellitus, receiving melatonin injections (10 mg/kg) starting on the 5th day post-alloxan for one week. Animals were euthanized by decapitation under light ether anesthesia on the 12th day of the experiment. Pyruvate levels in blood plasma were measured using standard methods. Statistical analysis was performed using Statistica 10 (StatSoft Inc.). Results. It is known that the presence of hyperglycemia under the conditions of diabetes intensifies the processes of free radical oxidation. According to the data obtained by us, in diabetic rats, a high level of glucose is accompanied by an increase in pyruvate in blood serum. This happens due to dysregulation of aerobic processes in the conditions of a decrease in insulin. In this case, pyruvate turns into lactate, creating conditions for the development of lactic acidosis. Staying under conditions of dark deprivation (light 24 hours) for a week led to a 15% increase in serum glucose and pyruvate levels in blood serum compared to intact animals. A similar situation was observed in a group of diabetic animals. Under conditions of round-the-clock lighting in diabetic animals, the indicators of glucose and pyruvate content increased even in comparison with the indicators of diabetic animals under equinox conditions and were on average 22% higher. However, exposure to light deprivation (24 hours of darkness) for a week led to a 10% decrease in glucose content and a 13% increase in pyruvate content when compared to intact animals. This happens due to the activation of the processes of aerobic oxidation of glucose under the conditions of an increase in melatonin. In diabetic rats, fasting pyruvate and glucose indicators under conditions of 24-hour darkness were negated by smaller deviations when compared with a group of diabetic animals that were under conditions of the equinox. It has been established that a short daytime photoperiod (8 hours of light: 16 hours of darkness) is characterized by an increase in melatonin secretion. Under these conditions, the indicators of antioxidant protection and the immune system improved in experimental animals. In addition, pinealectomized rats are characterized by reduced activity of glutathione peroxidase in tissues due to the absence of melatonin. The introduction of melatonin led to a decrease in glucose content in diabetic rats (under conditions of darkness - to normalization). The content of pyruvate in the blood serum of diabetic animals regardless of lighting conditions under the influence of melatonin injections did not differ from the control indicators under equinox conditions. The ability of melatonin to improve glucose uptake through glucose transporters has been investigated. In addition, there are data on melatonin as an activator of pyruvate dehydrogenase. It has been realised that melatonin has possibility to inhibit the activity of pyruvate dehydrogenase kinase and activate the pyruvate dehydrogenase thereby allowing the transformation of pyruvate to acetyl-CoA and sending glucose for oxidation in the mitochondria. Conclusion. Therefore, under both normal and diabetic conditions, melatonin enhances the efficiency of aerobic glucose oxidation pathways.

Melatonin Induces per1a Expression in Zebrafish Brain

In vertebrates, the circadian mechanism regulates many physiological and behavioral activities. The major key output of the circadian clock is the secretion of melatonin in the pineal gland. Melatonin secretion remains low during the daytime and increases significantly at night. The rise and fall of melatonin level is a key factor that conveys rhythmic information to the organism to carry out daily and annual physiological rhythms. It also affects the rhythmic oscillation of clock genes in the suprachiasmatic nucleus (SCN) as well as in peripheral tissues. In this study, we have shown that zebrafish brain rhythmically expresses per1a and cry1a in different photoperiodic regimes: light-dark cycle (LD) and continuous light (LL). We have also demonstrated that an acute injection of melatonin in the middle of the subjective day induces per1a expression in zebrafish brain. Furthermore, we have also shown that an acute injection of melatonin affects circadian regulation of locomotor activity in zebrafish under LD conditions. These results provide insight into understanding the underlying mechanism of melatonin in regulation of clock genes and locomotor activity in zebrafish.

Melatonin inhibits the activation of microglia and cough sensitivity of guinea pigs exposed to PM2.5.

The study aimed to examine the impact of melatonin on mitigating brain inflammation and cough sensitivity resulting from exposure to particulate matter 2.5 (PM2.5). Guinea pigs were randomly assigned to the blank control group, normal saline group, PM2.5 exposure group, and PM2.5 exposure + melatonin group. The PM2.5 exposure and PM2.5 exposure + melatonin groups were given intranasal instillations of PM2.5 suspension twice daily for 28 consecutive days. Starting on day 21, the PM2.5 exposure + melatonin group was treated with an intraperitoneal injection of melatonin at 10 pm. Cough sensitivity to citric acid, microglia activation, IL-1β and TNF-α levels in the airway and dorsal vagal complex (DVC), and ultrastructural changes in neurons within the DVC were assessed. The PM2.5 exposure group exhibited a significantly higher cough count to citric acid challenge (29.1±5.7 coughs) compared with the PM2.5 exposure + melatonin group (18.8±4.1 coughs), normal saline group (8.4±2.1 coughs), and blank control group (7.7±1.8 coughs). In addition, cough latency was shorter in the PM2.5 exposure group (26.9±6.5 seconds) than in the PM2.5 exposure + melatonin group (36.6±12.4 seconds), normal saline group (43.4±14.7 seconds), and blank control group (47.0±13.0 seconds). The PM2.5 exposure + melatonin group showed significantly reduced IL-1β (105.3±14.3 pg/ml) and TNF-α levels (113.0±23.5 pg/ml) in the DVC, as well as in the bronchoalveolar lavage fluid (IL-1β: 24.92±5.14 pg/ml, TNF-α: 12.72±3.99 pg/ml) compared with the PM2.5 exposure group (in the DVC: IL-1β: 132.7±17.6 pg/ml, TNF-α: 143.8±30.4 pg/ml; in the bronchoalveolar lavage fluid: IL-1β: 34.0±5.3 pg/ml; TNF-α: 15.8±0.8 pg/ml). Microglia in the DVC were less activated in the PM2.5 exposure + melatonin group (25.1±5.4) than in the PM2.5 exposure group (54.6±9.9). Furthermore, the PM2.5 exposure group exhibited an impaired blood-brain barrier in the DVC, which tended to alleviate the PM2.5 exposure + melatonin group. Exposure to PM2.5 induces airway inflammation, central facilitation, and heightened cough sensitivity in guinea pigs. Melatonin significantly inhibits microglia activation and reduces airway and DVC inflammation, which might contribute to attenuated cough hypersensitivity.

Melatonin attenuates degenerative disc degression by downregulating DLX5 via the TGF/Smad2/3 pathway in nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, and apoptosis plays a key role in its pathogenesis. Distal-less homeobox 5 (Dlx5) has been reported to induce cell apoptosis. Melatonin, as a powerful antiapoptotic agent, has been widely reported. This study aimed to investigate the role of DLX5 in the pathogenesis of IVDD and the potential therapeutic role of melatonin in targeting DLX5 in IVDD. Western blotting, RT-qPCR, immunohistochemistry, si-DLX5, Ex-DLX5, flow cytometry, and immunofluorescence were used to examine the regulatory effect of DLX5 on apoptosis. Therapeutic efficacy was assessed by the intraperitoneal injection of melatonin into IVDD mice. The expression level of DLX5 is significantly increased in IVDD, and the expression levels were positively correlated with the grade of IVDD. DLX5 was significantly upregulated in TNF-α-induced degenerative NP cells. Degenerative NP cells transfected with si-DLX5 exhibited significantly less apoptosis than control cells. Melatonin significantly alleviated IVDD in surgically induced IVDD model mice. The results revealed that the expression of DLX5 was positively correlated with the severity of IVDD and that melatonin ameliorated DLX5-induced apoptosis and extracellular matrix imbalance by inhibiting the TGF-β/Smad signaling pathway. This study may provide therapeutic strategies to alleviate inflammation-induced apoptosis IVDD-associated inflammation-induced apoptosis. DLX5 plays an important role in IVDD progression by promoting apoptosis, and melatonin represents a promising therapeutic strategy for alleviating IVDD-associated inflammation and apoptosis.

Transcriptomic analysis of melatonin on the mechanism of embryonic gonadal development in female Jilin white geese

The goose industry represents a significant sector within the broader waterfowl industry in China, with early gonadal development playing a pivotal role in enhancing population productivity. Melatonin plays a crucial role in regulating early gonadal development, but the molecular mechanism underlying the effect of melatonin as a regulator remains unclear. In this study, the relationship between melatonin and egg production performance in Jilin white goose was first established, then, an in Ovo injection of melatonin in goose embryos on the embryonic day 12 (E12) was performed to evaluate the impact of melatonin on the gonadal development in Jilin white goose. The results showed that the in Ovo injection of melatonin increased the expression of FOXL2 in the gonads while decreasing the expression of CYP19A1. Transcriptome analyses revealed that a total of 1184 differentially expressed genes were screened in Jilin white goose embryonic gonads among the two comparison groups. These DEGs were enriched in Gene Ontology (GO) terms related to the microtubule cytoskeleton, cytoskeleton, cell adhesion, and biological adhesion and the KEGG enrichment analysis suggested that the DEGs were mainly enriched in “MAPK signaling pathway”, “Wnt signaling pathway”, “Calcium signaling pathway”, “Focal adhesion”, “Neuroactive ligand-receptor interaction”, “Melanogenesis”, “mTOR signaling pathway”, “ECM-receptor interaction”, and “TGF-beta signaling pathway” in the two comparison groups. The protein-protein interaction network analysis (PPI) indicated that selected DEGs, such as PDIA3, ATCB, PKM, PGAM1, NME2, LDHB, and CALM2, were highly related to the regulation of the reproduction system development. Additionally, the expression trends of 4 identified DEGs were validated by RT-qPCR. In conclusion, this study elucidates the potential regulatory role of melatonin in gonadal development in geese, identifying candidate genes involved in early gonadal differentiation and maturation. Furthermore, the findings offer valuable practical implications for the goose industry, providing professionals with scientifically grounded strategies to enhance reproductive efficiency and overall population productivity.

Administration of melatonin nanoparticles improves testicular blood flow, echotexture of testicular parenchyma, scrotal circumference, and levels of estradiol and nitric oxide in prepubertal ossimi rams under summer heat stress.

Environmental heat stress (HS) impairs reproductive efficiency in farm animals. This study investigated, for the first time, how the melatonin and melatonin nanoparticles treatment affected the testicular hemodynamics, testicular volume, echotexture [Pixel intensity (PIX) and integrated density (IND)], scrotal circumference, serum concentration of testosterone (T), estradiol (E2), nitric oxide (NO), and total antioxidant capacity (TAC) in prepubertal Ossimi ram lambs in hot climatic conditions. The lambs undergoing examination had a temperature humidity index (THI) of 87.05 ± 1.70, indicating severe HS condition. Fifteen prepubertal Ossimi ram lambs were exposed to a single s.c injection of either nano melatonin (nano melatonin group; 20mg/ram; n = 5) or melatonin suspended in two ml of corn oil (melatonin group; 40mg/ram; n = 5) or two ml of corn oil (control group; n = 5). Blood collection and ultrasonographic assessment of the testes and supratesticular arteries (STAs) were conducted immediately before treatment (W0) and once weekly for six successive weeks after nano melatonin and melatonin injection (W1-W6). Results revealed decreases (P < 0.05) in the Doppler indices (resistive index; RI and pulsatility index; PI) of the testicular arteries at most time points of the study in the nano melatonin and melatonin groups. PIX of testicular parenchyma was significantly increased (P ˂ 0.05) in the treated groups compared to the control one. IND of testicular parenchyma increased significantly in the nano melatonin group compared to the melatonin and control groups. Testicular volume and scrotal circumference significantly increased (P < 0.05) in nano melatonin and melatonin groups compared to the control one. T concentration did not significantly (P > 0.05) change in the treated groups compared to the control group. E2, NO, and TAC concentrations increased (P < 0.05) in the treated groups compared to the control one. In conclusion, this study extrapolated that administrations of melatonin or nano melatonin can ameliorate the effects of environmental HS in prepubertal Ossimi ram lambs with a more protective effect and lower dose of nano melatonin.

Melatonin ameliorates chronic sleep deprivation against memory encoding vulnerability: Involvement of synapse regulation via the mitochondrial-dependent redox homeostasis-induced autophagy inhibition

Voluntary sleep curtailment is increasingly more rampant in modern society and compromises healthy cognition, including memory, to varying degrees. However, whether memory encoding is impaired after chronic sleep deprivation (CSD) and the underlying molecular mechanisms involved remain unclear. Here, using the mice, we tested the impact of CSD on the encoding abilities of social recognition-dependent memory and object recognition-dependent memory. We found that memory encoding was indeed vulnerable to CSD, while memory retrieval remained unaffected. The hippocampal neurons of mice with memory encoding deficits exhibited significant synapse damage and hyperactive autophagy, which dissipates during regular sleep cycles. This excessive autophagy appeared to be triggered by damage to mitochondrial DNA (mtDNA), resulting from oxidative stress within the mitochondria. The relief at the behavioral and molecular biological levels can be achieved with intraperitoneal injections of the antioxidant compound melatonin. Moreover, our in vitro experiments using HT-22 cells demonstrated that oxidative stress induced by hydrogen peroxide led to oxidative damage, including mtDNA damage, and activation of autophagy. Melatonin treatment effectively countered these effects, restoring redox homeostasis and reducing excessive autophagic activity. Notably, this protective effect was not observed when melatonin was administered as a pre-treatment. Together, our findings reveal the vulnerability of memory encoding during chronic sleep curtailment, which is caused by oxidative stress and consequent enhancement of autophagy, suggest a potential therapeutic strategy for addressing these effects following prolonged wakefulness through melatonin intervention, and reiterate the significance of adequate sleep for memory formation and retention.

Sustainable poultry practices: integrating green light interventions to control pecking in chicken

BackgroundThe present study aimed to investigate the impact of the light-emitting diode (LED) green light alone or in combination with melatonin on pecking-related hormone regulation during incubation under normal and under hormonal stress conditions in breeder eggs. This study was divided into 2 experiments: In the first experiment effect of LED green light incubation on pecking-related hormones under normal conditions, on Hy-line brown (low pecking phenotype) and Roman pink (high pecking phenotype) eggs were tested. The 296 eggs of each strain were divided into two groups: LED green light incubation and dark incubation (control), each containing four replicates (37 eggs/replicate). The second experiment was conducted to evaluate the effect of LED green light incubation alone or in combination with melatonin under hormonal stress conditions on Roman pink eggs. A total of 704 Roman pink eggs were taken and divided into four groups, each consisting of 176 eggs. Each group was further divided into 2 subgroups, LED green light-regulated incubation and dark incubation with 88 eggs per subgroup, having 4 replicates of 22 eggs each. The groups were as follows: corticosterone solution injection (CI), corticosterone + melatonin mixed solution injection (CMI), Phosphate buffer solution injection (PI), and no injection (UI).ResultsResults of the first experiment revealed a higher level of serotonin hormone and lower corticosterone hormone in Hy-Line brown embryos compared to Roman pink embryos during dark incubation. The LED green light incubation significantly (P < 0.05) increased the level of 5-HT while decreasing the CORT level in Roman pink embryos indicating its regulatory effect on pecking-related hormones. Results of the second experiment showed that LED green light incubation significantly (P < 0.05) alleviated the CORT-induced hyperactivity of plasma 5-HT in Roman pink embryos. Furthermore, Melatonin (MLT) injection and LED green light together significantly (P < 0.05) reduced the hormonal stress caused by corticosterone injection in the eggs.ConclusionsOverall, the LED green light regulatory incubation demonstrated a regulatory effect on hormones that influence pecking habits. Additionally, when coupled with MLT injection, it synergistically mitigated hormonal stress in the embryos. So, LED green light incubation emerged as a novel method to reduce the damaging pecking habits of poultry birds.

Short-Term Treatment of Melatonin Improves the Expression of Cell Adhesion Molecules in the Testis of the Mouse Cryptorchidism Model.

Melatonin plays a major role in regulating the sleep-wake cycle and enhancing testosterone production. We investigated the short-term effects of melatonin treatment for 14 consecutive days in the cryptorchidism model. We categorized experimental mice into Sham (S), Orchiopexy (O), Melatonin (Mel), and Orchiopexy + Melatonin (OMel) groups. Surgery involved inducing cryptorchidism in the left testis for seven days, followed by orchiopexy. The Mel group's testes did not descend, but they received melatonin injections after seven days of cryptorchidism. The OMel group underwent both orchiopexy and melatonin treatment. Both O and Mel groups exhibited decreased sperm and round-headed sperm in the epididymis. Significant increases were observed in the numbers of giant cells and negative Nectin-3 cells at p-value<0.05. The pattern of Cadm1 expression changed, and Nectin-2 and Nectin-3 co-expression was lacking in abnormal spermatids. Sertoli cell cytoplasm in both O and Mel groups exhibited autophagosomes and multivesicular bodies, which correlated with increased cyclooxygenase-2 expression. However, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell numbers increased significantly in all treatment groups compared to the S group. Our study found that the combination of orchiopexy and melatonin positively influenced the expression of cell adhesion molecules (Cadm1, Nectin-2, and Nectin-3) involved in spermatogenesis, while reducing giant cells, autophagosomes, and apoptosis.

Effects of red-light irradiation and melatonininjection on the antioxidant capacity and occurrence of apoptosis in abalones (Haliotis discus hannai) subjected to thermal stress

High ocean temperatures caused by global warming induce oxidative stress in aquatic organisms. Melatonin treatment and irradiation using red light-emitting diodes (LEDs) have been reported to reduce oxidative stress in a few aquatic organisms. However, the effects of red LED irradiation and melatonin injection on the antioxidant capacity and degree of apoptosis in abalones, which are nocturnal organisms, have not yet been reported. In this study, we compared the expression levels of antioxidant enzymes, total antioxidant capacity, and the degree of apoptosis in abalones subjected to red LED irradiation and melatonin treatment. The results revealed that at high water temperatures (25 °C), the mRNA expression levels of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) genes and the antioxidant activity of SOD decreased in abalones in the red-LED irradiated and melatonin-treated groups compared with those in abalones in the control group. Although high water temperatures induced DNA damage in the abalone samples, the degree of apoptosis was lower in the red-LED irradiated and melatonin-treated groups than in the control group. Overall, the abalones in the melatonin-treated and red-LED irradiated groups showed reduced oxidative stress and increased antioxidant enzyme levels under thermal stress compared with those in the control group. Therefore, red LED irradiation is a promising alternative to melatonin treatment, which is difficult to administer continuously for a long time, for protecting abalones from oxidative stress.

Effect of mesenchymal stem cells and melatonin on experimentally induced peripheral nerve injury in rats

Injury of a peripheral nerve (PNI) leads to both ischemic and inflammatory alterations. Sciatic nerve injury (SNI) represents the most widely used model for PNI. Mesenchymal stem cell-based therapy (MSCs) has convenient properties on PNI by stimulating the nerve regeneration. Melatonin has cytoprotective activity. The neuroprotective characteristics of MSCs and melatonin separately or in combination remain a knowledge need. In the rats-challenged SNI, therapeutic roles of intralesional MSCs and intraperitoneal melatonin injections were evaluated by functional assessment of peripheral nerve regeneration by walking track analysis involving sciatic function index (SFI) and two electrophysiological tests, electromyography and nerve conduction velocity, as well as measurement of antioxidant markers in serum, total antioxidant capacity (TAC) and malondialdehyde, and mRNA expression of brain derived neurotrophic factor (BDNF) in nerve tissues in addition to the histopathological evaluation of nerve tissue. Both individual and combination therapy with MSCs and melatonin therapies could effectively ameliorate this SNI and promote its regeneration as evidenced by improving the SFI and two electrophysiological tests and remarkable elevation of TAC with decline in lipid peroxidation and upregulation of BDNF levels. All of these led to functional improvement of the damaged nerve tissues and good recovery of the histopathological sections of sciatic nerve tissues suggesting multifactorial synergistic approach of the concurrent usage of melatonin and MSCs in PNI. The combination regimen has the most synergistic neuro-beneficial effects in PNI that should be used as therapeutic option in patients with PNI to boost their quality of life.

Investigation of the structural changes in the hippocampus and prefrontal cortex using FTIR spectroscopy in sleep deprived mice

Sleep is a basic, physiological requirement for living things to survive and is a process that covers one third of our lives. Melatonin is a hormone that plays an important role in the regulation of sleep. Sleep deprivation affect brain structures and functions. Sleep deprivation causes a decrease in brain activity, with particularly negative effects on the hippocampus and prefrontal cortex. Despite the essential role of protein and lipids vibrations, polysaccharides, fatty acid side chains functional groups, and ratios between amides in brain structures and functions, the brain chemical profile exposed to gentle handling sleep deprivation model versus Melatonin exposure remains unexplored. Therefore, the present study, aims to investigate a molecular profile of these regions using FTIR spectroscopy measurement’s analysis based on lipidomic approach with chemometrics and multivariate analysis to evaluate changes in lipid composition in the hippocampus, prefrontal regions of the brain. In this study, C57BL/6J mice were randomly assigned to either the control or sleep deprivation group, resulting in four experimental groups: Control (C) (n = 6), Control + Melatonin (C + M) (n = 6), Sleep Deprivation (S) (n = 6), and Sleep Deprivation + Melatonin (S + M) (n = 6). Interventions were administered each morning via intraperitoneal injections of melatonin (10 mg/kg) or vehicle solution (%1 ethanol + saline), while the S and S + M groups underwent 6 h of daily sleep deprivation from using the Gentle Handling method. All mice were individually housed in cages with ad libitum access to food and water within a 12-hour light–dark cycle. Results presented that the brain regions affected by insomnia. The structure of phospholipids, changed. Yet, not only changes in lipids but also in amides were noticed in hippocampus and prefrontal cortex tissues. Additionally, FTIR results showed that melatonin affected the lipids as well as the amides fraction in cortex and hippocampus collected from both control and sleep deprivation groups.

Lead specifically declines tyrosine hydroxylase activity to induce the onset of Parkinson's disease through disrupting dopamine biosynthesis in fly models

Parkinson's disease (PD) is one of the fastest-growing neurodegenerative diseases and has been linked to the exposure to numerous environmental neurotoxins. Although lead (Pb) exposure has been related to the development of PD, the molecular target of Pb to cause the onset of PD is insufficiently investigated. Herein, we explored the effects of Pb exposure on behavior, pathophysiology, and gene expression of wild-type (WT) fly (Drosophila melanogaster) by comparison with its PD model. After exposure to Pb, the WT flies showed PD-like locomotor impairments and selective loss of dopaminergic (DAergic) neurons, displaying similar phenotypes to fly PD model (PINK1). Transcriptomic analysis showed the similarity in gene expression profiles between Pb treatment WT flies and PINK1 mutant flies. Moreover, Pb exposure resulted in endogenous dopamine deficits in WT flies. Analyses of gene expression and enzyme activity confirmed that Pb exposure reduced tyrosine hydroxylase (TH) activity and led to failure of dopamine synthesis. Furthermore, molecular dynamics simulation confirmed that Pb was adsorbed by TH and subsequently inhibited the enzymatic activity. Exogenous injection of L-dopa and melatonin could partially rescue the pathological phenotypes of Pb-exposed flies and PD fly model. Antagonist injection of microRNA-133, which negatively regulated the expression of TH gene, ultimately rescued in the manifestation of PD phenotypes in flies. Involvement of TH overexpression mutants of fly strongly promoted the resistance to Pb exposure and rescued both behavior and the number of DAergic neurons. Therefore, our study elucidates the Pb molecular target in dopamine pathway and mechanism underlying the risks of Pb exposure on the occurrence of PD at environmentally-relevant concentrations.

Melatonin alleviates endoplasmic reticulum stress to improve ovarian function by regulating the mTOR pathway in aged laying hens

Granular cell apoptosis is a key factor leading to follicular atresia and decreased laying rate in aged laying hens. Endoplasmic reticulum stress (ERS) induced cell apoptosis is a new type of apoptosis pathway. Previous studies have shown that the ERS pathway is involved in the regulation of follicular development and atresia, and can be regulated by mTOR. Melatonin (MEL) can protect the normal development of follicles, but the precise mechanism by which MEL regulates follicular development is not yet clear. So, we investigated the potential relationship between MEL and ERS and mTOR signaling pathway in vivo through intraperitoneal injection of MEL in aged laying hens. The results show that the laying rate, ovarian follicle number, plasma MEL, E2, LH, FSH concentrations, as well as the mRNA expression of mTOR signaling-associated genes TSC1, TSC2, mTOR, 4E-BP1, and S6K in old later-period chicken control (Old-CN) group was significantly decreased (P < 0.01). In contrast, the ERS-related of plasma and granular cell layer mRNA expression of Grp78, CHOP, and Caspase-3 was significantly increased (P < 0.01). While both of the effects were reversed by MEL. Then, aging granulosa cells were treated with MEL in vitro, followed by RNA seq analysis, and it was found that 259 and 322 genes were upregulated and downregulated. After performing GO enrichment analysis, it was found that DEGs significantly contribute to the biological processes including cell growth and apoptosis. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to mTOR signaling and endoplasmic reticulum (ER) stress, involving genes such as GRB10, SGK1, PRKCA, RPS6KA2, RAF1, PIK3R3, FOXO1, DERL3, HMOX1, TLR7, VAMP7 and INSIG2. The obtained results of RT-PCR showed consistency with the RNA-Seq data. In summary, the underlined results revealed that MEL has significantly contributed to follicular development via activating the mTOR signaling pathway-related genes and alleviating ERS-related genes in laying hens. The current study provides a theoretical background for enhancing the egg-laying capability of hens and also providing a basis for elucidating the molecular mechanism of follicular selection.

Impact of melatonin administration on sperm quality, steroid hormone levels, and testicular blood flow parameters in small ruminants: A meta-analysis.

The impact of exogenous melatonin on the sperm quality of small ruminants is controversial. Therefore, this study aimed to synthesize previous findings on the influence of melatonin injection on sperm quality, steroid hormones, and testicular blood flow in small ruminants. Thirty studies were analyzed by computing the raw mean difference (RMD) as the effect size between the control and melatonin treatment groups, using the inverse of the variance for the random-effect model of the method of moments by DerSimonian and Laird. We assessed heterogeneity among studies using Q test. I2 statistic was used to classify the observed heterogeneity. We used Egger's regression method to indicate publication bias. Melatonin injection (p < 0.05) affected sperm concentration (RMD = 0.42 × 109/mL), morphology (RMD = 2.82%), viability (RMD = 2.83%), acrosome integrity (RMD = 4.26%), and DNA integrity (RMD = 1.09%). Total motility (RMD = 5.62%), progressive motility (RMD = 7.90%), acrosome integrity (RMD = 8.68%), and DNA integrity (RMD = 2.01%) of post-thawed semen in the melatonin-treated group were also increased (p < 0.05). Similarly, treatment with melatonin (p < 0.05) enhanced total motility (RMD = 5.78%), progressive motility (RMD = 5.28%), curvilinear velocity (RMD = 4.09 μm/s), straight-line velocity (RMD = 5.61 μm/s), and average path velocity (RMD = 4.94 μm/s). Testosterone (RMD = 1.02 ng/mL) and estradiol 17-ß levels (RMD = 0.84 pg/mL) were elevated (p < 0.05) in the melatonin-injected group. Melatonin implantation ameliorated testicular blood flow, as indicated by a significant reduction (p < 0.05) in the resistive index (RMD = 0.11) and pulsatility index (RMD = -0.15). Melatonin administration can increase the reproductive performance of small male ruminants.

Melatonin reduces lung injury in type 1 diabetic mice by the modulation of autophagy

BackgroundIn recent years, the role of autophagy has been highlighted in the pathogenesis of diabetes and inflammatory lung diseases. In this study, using a diabetic model of mice, we investigated the expression of autophagy-related genes in the lung tissues following melatonin administration.ResultsData showed histopathological remodeling in lung tissues of the D group coincided with an elevated level of IL-6, Becline-1, LC3, and P62 compared to the control group (p < 0.05). After melatonin treatment, histopathological remodeling was improved D + Mel group. In addition, expression levels of IL-6, Becline-1, LC3, and P62 were decreased in D + Mel compared to D group (P < 0.05). Statistically significant differences were not obtained between Mel group and C group (p > 0.05).ConclusionOur results showed that melatonin injection can be effective in the amelioration of lung injury in diabetic mice presumably by modulating autophagy-related genes.

Melatonin and its bioisosteres as potential therapeutic agents for the treatment of retinopathy of prematurity.

We conducted a study on the impact of intraperitoneal injections of melatonin and its three bioisosteres (compounds 1-3) on the development of oxygen-induced retinopathy in newborn rats during a 21-day experiment. It was demonstrated that melatonin and its analogues 1-3 effectively reduce the total protein concentration in the vitreous body of rat pups, decrease concentration of VEGF-A, and lower the level of oxidative stress (as indicated by normalization of antioxidant activity in the vitreous body). Melatonin and its analogues 1-3 equally normalize the level of VEGF-A. Analogues 1 and 2 even exceed melatonin in their ability to reduce protein influx into the vitreous body. However, analogue 2 had no effect on antioxidant activity, while analogues 1 and 3 caused a significant increase in this parameter, with analogue 3 even slightly exceeding melatonin. Thus, it can be concluded that analogues 1-3 are comparable to melatonin and can be utilized as potential therapeutic agents for the treatment of retinopathy of prematurity.

Melatonin injection and red light irradiation affect the antioxidant response and cell damage in disk abalone (Haliotis discus hannai) exposed to high water temperatures.

The effects of red light-emitting diode (LED) light irradiation (630 nm, 0.5 W/m2) and melatonin (10-8 and 10-7 M) on oxidative stress and physiological responses in abalones exposed to high temperatures (28°C) were investigated. Changes in messenger RNA (mRNA) expressions of melatonin receptor (MT-R), heat shock protein 70 (HSP70), and antioxidant enzymes, as well as alterations in H2O2 levels in the hemolymph, were examined. The results revealed that high-temperature-stressed abalones treated with melatonin injections or exposed to red LED light showed a significant increase in MT-R mRNA expression, while HSP70 mRNA expression decreased. Notably, HSP70 mRNA expression levels in the red LED light-irradiated group were similar to those in the group injected with 10-8 M melatonin after 24 h exposure. Abalones treated with melatonin at 20°C or irradiated with red LED light exhibited decreased H2O2 levels and reduced antioxidant enzyme mRNA expression compared with those of the control group. However, the high-temperature environment induced oxidative stress in abalones, leading to increased antioxidant enzyme mRNA expression compared with that under 20°C conditions. Moreover, abalones exposed to high-temperature stress exhibited hepatopancreatic DNA damage, which was attenuated by melatonin treatment or red LED light irradiation. Hence, red LED light reduces oxidative stress, boosts antioxidant enzymes, and alleviates DNA damage in high-temperature-stressed abalones, akin to 10-8 M melatonin treatment. Therefore, considering the practical challenges of continuous melatonin administration to abalones, utilizing red LED light emerges as a practical, effective alternative to protect abalones from oxidative stress compared to 10-8 M melatonin treatment.