Protective Effect Of Melatonin Research Articles

Cuproptosis is involved in decabromodiphenyl ether-induced ovarian dysfunction and the protective effect of melatonin

Decabromodiphenyl ether (BDE-209) has been universally detected in environmental media and animals, but its damage to ovarian function and mechanism is still unclear, and melatonin has been shown to improve mammalian ovarian function. This study aimed to investigate the toxic effects of BDE-209 on the ovary and tried to improve ovarian function with melatonin. Herein, BDE-209 was administered orally to female SD rats for 60 days. Enzyme-linked immunosorbent assay, HE staining, transcriptome analysis, qPCR and immunohistochemical staining were used to explore and verify the potential mechanism. We found that BDE-209 exposure had effects on the ovary, as shown by abnormal changes in the estrous cycle, hormone levels and ovarian reserve function in rats, while increasing the proportion of collagen fibres in ovarian tissue. In terms of mechanism, cuproptosis, a form of cell death, was identified to play a crucial role in BDE-209-induced ovarian dysfunction, with the phenotype manifested as copper salt accumulation in ovary, downregulation of glutathione pathway metabolism and copper transfer molecule (ATP7A/B), and upregulation of FDX1, lipoic acid pathway (LIAS, LIPT1), pyruvate dehydrogenase complex components (DLAT, PDHB, PDHA1), and copper transfer molecule (SLC31A1). Furthermore, possible interventions were explored. Notably, a supplement with melatonin has a repair effect on the damage to ovarian function by reversing the gene expression of cuproptosis-involved molecules. Overall, this study revealed that cuproptosis is involved in BDE-209-induced ovarian damage and the beneficial effect of melatonin on ovarian copper damage, providing evidence for the prevention and control of female reproductive damage induced by BDE-209.

Protective effect of melatonin on imidacloprid-induced pyroptosis and ferroptosis by mediating peptidoglycan in the gut of the common carp (Cyprinus carpio)

Imidacloprid (IMI) is a contaminant widespread in surface water, causing serious intestinal damage in the common carp. Melatonin (MT), an endogenous indoleamine hormone, plays a crucial role in mitigating pesticide-induced toxicity. Our previous research has demonstrated that MT effectively reduces the production of intestinal microbial-derived signal peptidoglycan (PGN) induced by IMI, thereby alleviating intestinal tight junction injuries in the common carp. In this study, we performed a transcriptomic analysis to explore the effect of MT on the IMI exposure-induced gut damage of the common carp. The results elucidated that the ferroptosis, mitogen-activated protein kinases (MAPKs), and nucleotide oligomerization domain (NOD)-like signaling pathways were significantly associated with IMI exposure and MT treatment. Meanwhile, the exposure to IMI resulted in the formation of pyroptotic bodies and distinct morphological features of ferroptosis, both mitigated with the addition of MT. Immunofluorescence double staining demonstrated that MT abolished the elevated expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin D (GSDMD) induced by IMI, as well as reduced expression of ferritin heavy chains (FTH) and glutathione peroxidase 4 (GPX4) in gut tissues. Subsequently, we found that the exposure to IMI or PGN enhanced the expression of toll-like receptors (TLR) 2 (a direct recognition receptor of PGN) triggering the P38MAPK signaling pathway, thereby aggravating the process of pyroptosis and ferroptosis of cell models. The addition of MT or SB203580 (a P38MAPK inhibitor) significantly reduced pyroptotic cells, and also decreased iron accumulation. Consequently, these results indicate that MT alleviates IMI-induced pyroptosis and ferroptosis in the gut of the common carp through the PGN/TLR2/P38MAPK pathway.

Protective Effects of Melatonin against Carcinogen-Induced Oxidative Damage in the Thyroid.

Melatonin, primarily synthesized in the pineal gland, plays a crucial role in regulating circadian rhythms and possesses significant antioxidative properties. By neutralizing free radicals and reducing oxidative stress, melatonin emerges as a promising agent for the prevention and therapy of many different disorders, including cancer. This paper reviews the relationship between the thyroid gland and melatonin, presenting experimental evidence on the protective effects of this indoleamine against oxidative damage to macromolecules in thyroid tissue caused by documented carcinogens (as classified by the International Agency for Research on Cancer, IARC) or caused by potential carcinogens. Furthermore, the possible influence on cancer therapy in humans and the overall well-being of cancer patients are discussed. The article highlights melatonin's essential role in maintaining thyroid health and its contribution to management strategies in patients with thyroid cancer and other thyroid diseases.

Protective effects of melatonin on AT1, ACE2, and Mas genes expression in induced diabetic aortic rats

Protective effects of melatonin on AT1, ACE2, and Mas genes expression in induced diabetic aortic rats

Melatonin modulates lipopolysaccharides-induced inflammatory response and maintains circadian rhythm associated with histone H3 acetylation in bovine mammary epithelial cells

Lipopolysaccharides (LPS) can disrupt the barrier function of mammary epithelial cells, leading to mastitis. The protective effects of melatonin (MT) have been demonstrated against various infections, but the underlying mechanism remains unclear in LPS-induced bovine mastitis. This study, therefore, aimed to investigate the modulatory effect of melatonin (MT) on LPS-induced inflammation in bovine mammary epithelial cells (BMECs), its influence on the disruption of circadian rhythms triggered by this inflammation, and the potential underlying molecular mechanisms. BMECs extracted from lactating cows underwent one of 4 treatments in triplicates for 12 h simultaneously: Control (CON), LPS (exposed to LPS at 1 μg/mL), MT (exposed to MT at 40 μmol/L), or LPS + MT (LMT, exposed to both LPS at 1 μg/mL and MT at 40 μmol/L). The flow cytometry results demonstrated that MT reduced the ratios of cells in the G0/G1 phase but increased those in the G2/M phase (P < 0.05). Additionally, MT inhibited p65 phosphorylation levels, leading to a decreased cellular inflammatory response (P < 0.05). Treatment with MT elevated the acetylation levels of histone H3 in BMECs compared to the LPS treatment (P < 0.05). The circadian rhythm analysis revealed a significant increase in the gene expression levels of BMAL1, PER1, CRY1, and CRY2 at the 12 h mark in LMT compared to the LPS treatment (P < 0.05). Additionally, this study assessed the fluctuations in clock-related genes PER2 and CLOCK over 24 h under various treatment conditions. The results demonstrated that BMECs exposed to LMT treatment exhibited a significant increase in the expression levels of CLOCK and PER2 genes from 4 to 24 h in comparison to the LPS treatment (P < 0.05). Moreover, cells in the LMT treatment displayed a more regular circadian rhythm cycle compared to those in the LPS treatment. Overall, the data suggest that MT could alleviate the inflammatory response in BMECs by upregulating histone H3 acetylation, thereby maintaining the physiological circadian rhythm of BMECs.

Effect of platelet rich plasma versus melatonin on testicular injury induced by Busulfan in adult albino rats: a histological and immunohistochemical study

ABSTRACT This study was done to estimate the testicular histological alterations induced by Busulfan (BUS) and compare the possible protective effects of melatonin (MT) and platelet rich plasma (PRP) in a rat model. Sixty-four male rats were dispersed into: control group, BUS group, melatonin group, and PRP group. Blood samples were processed for biochemical analysis. Tissue specimens were managed for light and electron microscopic studies. Immunohistochemical expression of vimentin and proliferating cell nuclear antigen (PCNA) was performed. Busulfan induced severe testicular damage in all studied methodologies. It showed a statistically significant decrease in serum testosterone and elevation of MDA when compared to the control group. Abnormal testicular cytostructures suggesting defective spermatogenesis were observed: distorted seminiferous tubules, deformed spermatogenic cells, low germinal epithelium height, few mature spermatozoa, and also deformed barrier. Vimentin and PCNA expressions were reduced. Ultrastructurally, Sertoli cells and the blood testis barrier were deformed, spermatogenic cells were affected, and mature spermatozoa were few and showed abnormal structure. Both melatonin and PRP induced improvement in all the previous parameters and restoration of spermatogenesis as confirmed by improvement of Johnsen’s score from 2.6 ± .74 to 7.6 ± .92. In conclusion, melatonin and PRP have equal potential to ameliorate the testicular toxicity of BUS. Melatonin can provide a better noninvasive way to combat BUS induced testicular injury.

Melatonin Modulates Cell Cycle Dynamics and Promotes Hippocampal Cell Proliferation After Ischemic Injury in Neonatal Rats.

Promoting neural cell proliferation may represent an important strategy for enhancing brain repair after developmental brain injury. The present study aimed to assess the effects of melatonin on cell proliferation after an ischemic injury in the developing hippocampus, focusing on cell cycle dynamics. After in vivo neonatal hypoxia-ischemia (HI), hippocampal cell cycle dynamics were assessed by flow cytometry, together with histological evaluation of dentate gyrus cellularity and proliferation. Melatonin significantly increased the number of proliferating cells in the G2/M phase as well as the proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) labeling reduced by HI. In vivo BrdU labeling revealed a higher BrdU-positivity in the dentate gyrus of ischemic rats treated with melatonin, an effect followed by increased cellularity and preserved hippocampal tissue integrity. These results indicate that the protective effect of melatonin after ischemic injury in neonatal rats may rely on the modulation of cell cycle dynamics of newborn hippocampal cells and increased cell proliferation.

Melatonin ameliorates retinal ganglion cell senescence and apoptosis in a SIRT1-dependent manner in an optic nerve injury model

Melatonin is involved in exerting protective effects in aged-related and neurodegenerative diseases through a silent information regulator type 1 (SIRT1)-dependent pathway. However, little was known about the impact of melatonin on retinal ganglion cell (RGC) senescence and apoptosis following optic nerve crush (ONC). Thus, this study aimed to examine the effects of melatonin on RGC senescence and apoptosis after ONC and investigate the involvement of SIRT1 in this process. To study this, an ONC model was established. EX-527, an inhibitor of SIRT1, was injected intraperitoneally into mice. And melatonin was administrated abdominally into mice after ONC every day. Hematoxylin & eosin staining, retina flat-mounts and optical coherence tomography were used to evaluate the loss of retina cells/neurons. Pattern electroretinogram (p-ERG) was performed to evaluate the function of RGCs. Immunofluorescence and western blot were used to evaluate protein expression. SA-β-gal staining was employed to detect senescent cells. The results demonstrated that melatonin partially rescued the expression of SIRT1 in RGC 3 days after ONC. Additionally, melatonin administration partly rescued the decreased RGC number and ganglion cell complex thickness observed 14 days after ONC. Melatonin also suppressed ONC-induced senescence and apoptosis index. Furthermore, p-ERG showed that melatonin improved the amplitude of P50, N95 and N95/P50 following ONC. Importantly, the protective effects of melatonin were reversed when EX-527 was administered. In summary, this study revealed that melatonin attenuated RGC senescence and apoptosis through a SIRT1-dependent pathway after ONC. These findings provide valuable insights for the treatment of RGC senescence and apoptosis.

IP3R1-mediated MAMs formation contributes to mechanical trauma-induced hepatic injury and the protective effect of melatonin

IntroductionThere is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs.MethodsHepatic mechanical injury was established in Sprague–Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, apoptosis, MAMs formation, mitochondrial function and signaling pathways.ResultsSignificant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 μmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin’s inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation.ConclusionMelatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury.Graphical

Melatonin alleviates high temperature exposure induced fetal growth restriction via the gut-placenta-fetus axis in pregnant mice

IntroductionGlobal warming augments the risk of adverse pregnancy outcomes in vulnerable expectant mothers. Pioneering investigations into heat stress (HS) have predominantly centered on its direct impact on reproductive functions, while the potential roles of gut microbiota, despite its significant influence on distant tissues, remain largely unexplored. Our understanding of deleterious mechanisms of HS and the development of effective intervention strategies to mitigate the detrimental impacts are still limited. ObjectivesIn this study, we aimed to explore the mechanisms by which melatonin targets gut microbes to alleviate HS-induced reproductive impairment. MethodsWe firstly evaluated the alleviating effects of melatonin supplementation on HS-induced reproductive disorder in pregnant mice. Microbial elimination and fecal microbiota transplantation (FMT) experiments were then conducted to confirm the efficacy of melatonin through regulating gut microbiota. Finally, a lipopolysaccharide (LPS)-challenged experiment was performed to verify the mechanism by which melatonin alleviates HS-induced reproductive impairment. ResultsMelatonin supplementation reinstated gut microbiota in heat stressed pregnant mice, reducing LPS-producing bacteria (Aliivibrio) and increasing beneficial butyrate-producing microflora (Butyricimonas). This restoration corresponded to decreased LPS along the maternal gut-placenta-fetus axis, accompanied by enhanced intestinal and placental barrier integrity, safeguarding fetuses from oxidative stress and inflammation, and ultimately improving fetal weight. Further pseudo-sterile and fecal microbiota transplantation trials confirmed that the protective effect of melatonin on fetal intrauterine growth under HS was partially dependent on gut microbiota. In LPS-challenged pregnant mice, melatonin administration mitigated placental barrier injury and abnormal angiogenesis via the inactivation of the TLR4/MAPK/VEGF signaling pathway, ultimately leading to enhanced nutrient transportation in the placenta and thereby improving the fetal weight. ConclusionMelatonin alleviates HS-induced low fetal weight during pregnancy via the gut-placenta-fetus axis, the first time highlighting the gut microbiota as a novel intervention target to mitigate the detrimental impact of global temperature rise on vulnerable populations.

1,2-Dichloroethane induces testicular pyroptosis by activating piR-mmu-1019957/IRF7 pathway and the protective effects of melatonin

1,2-Dichloroethane (1,2-DCE) is a prevalent environmental contaminant, and our study revealed its induction of testicular toxicity in mice upon subacute exposure. Melatonin, a prominent secretory product of the pineal gland, has been shown to offer protection against pyroptosis in male reproductive toxicity. However, the exact mechanism underlying 1,2-DCE-induced testicular toxicity and the comprehensive extent of melatonin's protective effects in this regard remain largely unexplored. Therefore, we sequenced testis piRNAs in mice exposed to environmentally relevant concentrations of 1,2-DCE by 28-day dynamic inhalation, and investigated the role of key piRNAs using GC-2 spd cells. Our results showed that 1,2-DCE induced mouse testicular damage and GC-2 spd cell pyroptosis. 1,2-DCE upregulated the expression of pyroptosis-correlated proteins in both mouse testes and GC-2 spd cells. 1,2-DCE exposure caused pore formation on cellular membranes and lactate dehydrogenase leakage in GC-2 spd cells. Additionally, we identified three upregulated piRNAs in 1,2-DCE-exposed mouse testes, among which piR-mmu-1019957 induced pyroptosis in GC-2 spd cells, and its inhibition alleviated 1,2-DCE-induced pyroptosis. PiR-mmu-1019957 mimic and 1,2-DCE treatment activated the expression of interferon regulatory factor 7 (IRF7) in GC-2 spd cells. IRF7 knockdown reversed 1,2-DCE-induced cellular pyroptosis, and overexpression of piR-mmu-1019957 did not promote pyroptosis when IRF7 was inhibited. Notably, melatonin reversed 1,2-DCE-caused testicular toxicity, cellular pyroptosis, and upregulated piR-mmu-1019957 and IRF7. Collectively, our findings indicated that melatonin mitigates this effect, suggesting its potential as a therapeutic intervention against 1,2-DCE-induced male reproductive toxicity in clinical practice.

Protective effect of melatonin against amyloid-beta-induced damage in model lipid membranes

Protective effect of melatonin against amyloid-beta-induced damage in model lipid membranes

Protective Effects of Melatonin and Captopril against Cardiac Oxidative Stress and Dysfunction Induced by Nicotine in Rats

Protective Effects of Melatonin and Captopril against Cardiac Oxidative Stress and Dysfunction Induced by Nicotine in Rats

Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A.

Pregnancy is a highly intricate and delicate process, where inflammation during early stages may lead to pregnancy loss or defective implantation. Melatonin, primarily produced by the pineal gland, exerts several pharmacological effects. N6-methyladenosine (m6A) is the most prevalent mRNA modification in eukaryotes. This study aimed to investigate the association between melatonin and m6A during pregnancy and elucidate the underlying protective mechanism of melatonin. Melatonin was found to alleviate lipopolysaccharide (LPS)-induced reductions in the number of implantation sites. Additionally, it mitigated the activation of inflammation, autophagy, and apoptosis pathways, thereby protecting the pregnancy process in mice. The study also revealed that melatonin regulates uterine m6A methylation levels and counteracts abnormal changes in m6A modification of various genes following LPS stimulation. Furthermore, melatonin was shown to regulate m6A methylation through melatonin receptor 1B (MTNR1B) and subsequently modulate inflammation, autophagy, and apoptosis through m6A. In conclusion, our study demonstrates that melatonin protects pregnancy by influencing inflammation, autophagy, and apoptosis pathways in an m6A-dependent manner via MTNR1B. These findings provide valuable insights into the mechanisms underlying melatonin's protective effects during pregnancy and may have implications for potential therapeutic strategies in managing pregnancy-related complications.

Melatonin's Protective Effects on Neurons in an in Vitro Cell Injury Model.

Currently, the role of melatonin (MT) in neuronal damage remains unclear and this study aimed to explore the protective effects of MT on neurons in an in vitro cell injury model. The Sprague Dawley (SD) rat traumatic brain injury (TBI) model was prepared, and brain tissue extract (BTE) from the injured area were generated. To establish a cell injury model in vitro, the BTE was added to the culture medium during the neuron culture process. MT was introduced into the culture medium of the cell injury model to observe its protective effects on neurons. Relevant molecular biology experiments were conducted to observe cellular oxidative stress status, inflammation, endoplasmic reticulum (ER) stress, mitochondrial damage, and neuronal apoptosis. When compared to the control group, the BTE group exhibited a significant increase in cellular oxidative stress, inflammation, neurofilament light polypeptide (NEFL) expression, and ER stress. Additionally, the mitochondrial DNA (mtDNA) copy number significantly decreased, and there was a higher count of apoptotic cells (p < 0.05). Upon the addition of MT to the culture medium of the in vitro cell injury model, there was a significant reduction in cellular oxidative stress, inflammation, and NEFL levels. This addition also mitigated ER stress, increased mtDNA copy numbers, and decreased the ratio of cell apoptosis (p < 0.05). In the in vitro cell injury model, MT demonstrates the capacity to inhibit cellular oxidative stress, inflammation, and ER stress levels. Additionally, it diminishes mtDNA damage, fosters cell viability, and serves as a protective agent against both apoptosis and necrosis in neurons.

The therapeutic potential of melatonin against hepatotoxicity caused by obesity and NSAIDs: A comprehensive review

The obesity and increased free fatty acid level are considered the etiology of hepatotoxicity leading to steatohepatitis and hepatic fibrosis. Obesity promotes inflammatory response and oxidative stress. Adipocytes secrete various proinflammatory cytokines including TNF-α, IL-1β, IL-6 and leptin to initiate a vicious cycle and cause further fat accumulation and weight gain. Specifically, to liver, the fat accumulation will cause non-alcoholic fatty liver disease (NAFLD), the most prevailing chronic liver ailment, if it is not properly treated, then it will cause severe outcomes including fatality. In addition, obesity also cause other inflammatory disorders including osteoarthritis of the knee, joint pain, etc. Non-steroidal anti-inflammatory drugs (NSAIDs) are most often used medicines for treatment of inflammation but their serious side effects are concerning. These include gastric mucosal damage, liver injury with elevated aminotransferase (AST/ALT) levels, hepatitis, jaundice and more fatal liver diseases. Melatonin, an antioxidant and anti-inflammatory molecule can be used to treat diverse kind of inflammatory diseases. It remarkably reduces the mRNA levels of pro-inflammatory cytokines of TNF-α, IL-6, IL-1β, etc. Melatonin and its metabolites retain the properties as an effective free radical scavenger and regulate various antioxidative and pro-oxidative enzymes. This molecule can potentially abate the ill effects of hepatotoxicity induced by both NSAIDs and obesity. Therefore, this review briefly summarizes the recent available knowledge on the protective effects of melatonin against various disorders involving weight gain and hepatotoxicity.

The ROS/SIRT1/STAR axis as a target for melatonin ameliorating atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells

The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.

Protective effects of melatonin in a novel rat model of post-stroke epilepsy

Protective effects of melatonin in a novel rat model of post-stroke epilepsy

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress.

Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

Protective effect of melatonin on blood-brain barrier damage caused by Endotoxemia

ABSTRACT Objective Endotoxins, products of Gram-negative bacteria, are the primary cause of blood-brain barrier (BBB) damage. In the present study, we aimed to investigate the possible neuroprotection mechanisms of melatonin on BBB damage induced by endotoxemia. Methods Adult, female Sprague-Dawley rats (n = 42) were separated into four random groups as a control group and three treatment groups. Lipopolysaccharide (7,5 mg/kg/day) was administrated for a single dose to generate a 24-hour sepsis model on rats. Melatonin (10 mg/kg/day) was treated a week before sepsis. Afterward, the dissected brain tissues were examined by histopathological, biochemical, and molecular analyses. Results LPS caused weight loss in the groups. As a result, degenerated neurons with cytoplasmic vacuoles and irregular pyknotic nuclei, pale stained necrotic neurons, and vascular congestion were observed in LPS-exposed rats. However, MEL decreased the number of degenerated neurons in treated groups. MEL treatment increased ZO1 and Occludin immunoreactivity while decreasing TLR4 in brain tissues. MEL effect on protein expression was recorded for ZO1 increase and TLR4 decrease in brain tissue compared to LPS groups. MEL also decreased MDA levels in brain tissue. Conclusions MEL recovered the degenerative damage of sepsis by contributing to blood-brain barrier integrity, and by decreasing inflammation, thus the neuroprotective effects of MEL might provide an experimental basis for clinical applications.