Pineal Research Articles

Морфологічні структури циркумвентрикулярного комплексу (Morphological structures of the circumvetricular complex)

Brain homeostasis requires the maintenance of barriers between the brain and the periphery, which are provided by brain microvessels in the blood-brain barrier and epithelial cells in the choroid plexus. Circumventricular complex (CVC) – structures located around the third and fourth ventricles, lining the cavity of the third ventricle (neurohypophysis, vascular organ of the end plate, epiphysis, subvault and subcommissural organs) and the fourth ventricle (posterior region), different from other structures of the brain due to the maximum vascularization and the absence of a typical blood-brain barrier. The subcommissural organ and the area postrema are located at the confluence between the ventricles, while the neurohypophysis, the vascular organ of the terminal plate, and the pineal gland line the ventricular depressions. All structures of the central nervous system are divided into sensory and secretory. Vessels in the CVC branch into a network of fenestrated capillaries with loosely connected astrocytic ends, which allows them to be considered as gates» to the brain; substances are transported by blood and freely leave the capillary lumen. Neurons and glial cells of the CVC form a unique symbiosis of receptors and ion channels, receiving chemical signals from the bloodstream. CVCs are described as the «windows of the brain» that form the blood-CSF barrier on the ventricular wall, which is composed of tanycyte-like cells that line the ventricular ependyma. Astrocytes and tanycytes form a dense barrier in the distal part of the CVC, preventing the free diffusion of the molecules obtained. from the blood to the neighboring areas of the brain. The barrier in front of the fenestrated vessels of the CVC may limit molecules carried by the blood through these «windows of the brain» and prevent their diffusion into the cerebrospinal fluid. In the central nervous system, connections between the central nervous system and peripheral blood flow serve as an alternative route for peptides and hormones of nervous tissue into the bloodstream, primarily performing neuroimmune-endocrine functions, as well as the role of an «immune watchman». Key words: circumventricular complex, cerebrospinal fluid, brain, blood-brain barrier.

Ramelteon protects against social defeat stress-associated abnormal behaviors

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.

Seasonal variation of melatonin secretion across various segments of the gastrointestinal tract in rats

ObjectiveTo investigate whether melatonin (MT) secretion in different parts of the gastrointestinal tract (GIT) exhibits seasonal variations and its correlation with immune regulation. MethodsSixty Sprague-Dawley rats were divided into control and model groups, and the pineal gland was removed in the model group. Stomach, jejunum, ileum, and colon tissues were obtained during the spring equinox, summer solstice, beginning of autumn, autumn equinox, and winter solstice. The levels of MT, MT receptors (MR), arylalkylamine N-acetyltransferase (AANAT), hydroxyindole-O-methyltransferase (HIOMT), interleukin-2 (IL-2), and interleukin-10 (IL-10) in the GIT were measured using enzyme-linked immunosorbent assay. ResultsExcept for the stomach, the jejunum, ileum, and the colon showed seasonal tendencies in MT secretion. In the control group, MT secretion in the jejunum and ileum was the highest in the long summer, and colonic MT secretion was the highest in winter. In the model group, MT levels in the colon were highest in the summer. The seasonal rhythms of the MR, AANAT, HIOMT, IL-2, and IL-10 in the colon were roughly similar to those of MT, and changed accordingly after pinealectomy. ConclusionsGastrointestinal MT secretion is related to seasonal changes, and MT secretion in each intestinal segment is influenced by different seasons. The biological effects of MT in the gut are inextricably linked to the mediation of MR, and a hormone-receptor linkage exists between MT and MR. The effect of seasonal changes on the gastrointestinal immune system may be mediated through the regulation of seasonal secretion of MT.

The Role and Therapeutic Potential of Melatonin in Degenerative Fundus Diseases: Diabetes Retinopathy and Age-Related Macular Degeneration.

Degenerative fundus disease encompasses a spectrum of ocular diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), which are major contributors to visual impairment and blindness worldwide. The development and implementation of effective strategies for managing and preventing the onset and progression of these diseases are crucial for preserving patients' visual acuity. Melatonin, a neurohormone primarily produced by the pineal gland, exhibits properties such as circadian rhythm modulation, antioxidant activity, anti-inflammatory effects, and neuroprotection within the ocular environment. Furthermore, melatonin has been shown to suppress neovascularization and reduce vascular leakage, both of which are critical in the pathogenesis of degenerative fundus lesions. Consequently, melatonin emerges as a promising therapeutic candidate for degenerative ocular diseases. This review provides a comprehensive overview of melatonin synthesis, its localization within ocular tissues, and its mechanisms of action, particularly in regulating melatonin production, thereby underscoring its potential as a therapeutic agent for degenerative fundus diseases.

Pineal gland: Sleep, malignancy and statistics.

e14042 Background: The pineal gland is a neuroendocrine gland located deep in the middle brain that regulates the circadian rhythm through Melatonin. Pineal parenchymal tumors arise from pineocytes, have no sexual predominance, occur most frequently in the pediatric population and result in melatonin level disruptions.Pineal region tumors can spread via CSF to other areas in the CNS. The first treatment for pineal region tumors is surgery. Treatments after surgery may include radiation, chemotherapy or clinical trials. Methods: Data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). Pineal gland tumor cases that were labeled as the primary site were extracted from the data base. Further selection was made using the ICD Code D75.3 for neoplasm of pineal gland-primary site labelled. The data was stratified based on age, sex, race and survival curves were compared using the Log-Rank test (GraphPad Prism). Results: A total of 416 pineal gland tumor cases were found, of which ~ 50.48% were males. These tumors were most commonly seen in White (51.68%) patients followed by Hispanic (23.32%), Black (16.10%), Asians/Pacific Islander (6.97%) and Alaskans/Native American (0.96%) patients. The median age of diagnosis was 24.5 years. The incidence rate (per 1,000,000 population) for the general population has increased from 0.69 in 2000 to 0.73 in 2020. As of 2020, the incidence was noted to be higher in males, although overall the incidence among females has been ion the rise. Incidence rate was highest among the Native Americans/Alaskans population followed by Hispanics, Asians/Pacific Islanders, Blacks and Whites. Within the races, incidence was noted to be increasing in the Native Americans/Alaskans & Hispanic populations, stable in the Asians/Pacific Islanders & Black populations and decreasing amongst the White population over the period of 20 years. When the survival curves were compared on the basis of gender and race, the data was clinically significant only for gender. The median of survival (mOS) for males was 146 months but was undefined for females (CI:5.344-12.55, HR: 8.191, p <0.0001) mostly likely due to zero death events being recorded for females. Conclusions: Pineal gland tumors are rarely encountered malignancy with only 416 case reported in the last two decades. It has an almost equal predilection for males and females, more common in the younger population. The incidence is higher among males, although being relatively constant since 2000, and is trending up in females. Overall survival was superior in females with no reported death events. Native Americans/Alaskans are more affected overall survival is independent of the race.

Therapeutic Effects of Melatonin in the Regulation of Ferroptosis: A Review of Current Evidence.

Ferroptosis is implicated in the pathogenesis of multiple diseases, including neurodegenerative diseases, cardiovascular diseases, kidney pathologies, ischemia-reperfusion injury, and cancer. The current review article highlights the involvement of ferroptosis in traumatic brain injury, acute kidney damage, ethanol-induced liver injury, and PM2.5-induced lung injury. Melatonin, a molecule produced by the pineal gland and many other organs, is well known for its anti- aging, anti-inflammatory, and anticancer properties and is used in the treatment of different diseases. Melatonin's ability to activate anti-ferroptosis pathways including sirtuin (SIRT)6/p- nuclear factor erythroid 2-related factor 2 (Nrf2), Nrf2/ antioxidant responsive element (ARE)/ heme oxygenase (HO-1)/SLC7A11/glutathione peroxidase (GPX4)/ prostaglandin-endoperoxide synthase 2 (PTGS2), extracellular signal-regulated kinase (ERK)/Nrf2, ferroportin (FPN), Hippo/ Yes-associated protein (YAP), Phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) and SIRT6/ nuclear receptor coactivator 4 (NCOA4)/ ferritin heavy chain 1 (FTH1) signaling pathways suggests that it could serve as a valuable therapeutic agent for preventing cell death associated with ferroptosis in various diseases. Further research is needed to fully understand the precise mechanisms by which melatonin regulates ferroptosis and its potential as a therapeutic target.

Emergency treatment for primary intracranial germ cell tumours (PICGCTs).

e17020 Background: PICGCTs arise de novo in children and young adults, most frequently in the pineal or suprasellar regions. Here, we evaluate the acute pathway for patients (pts) with PICGCTs managed at our Emergency Cancer Treatment Centre. Methods: Retrospective observational study from 1984-2022 at a single institution. Data was collected from paper and electronic patient records for all PICGCT pts, including pts treated with our intracranial regimen EP-OMB (Etoposide-Cisplatin alternating every week with Vincristine-Methotrexate-Bleomycin) administered with and without intrathecal Methotrexate. Results: To date, we have identified 43 pts with intracranial disease treated at our Centre over 38 years: 25 pts (58%) with PICGCT, 18pts (42%) with germ cell tumour brain metastases treated with EP-OMB and excluded from analysis. Most PICGCT pts are male (92%, n=23) with a median age 25 (range 17-50). The majority present with symptomatic disease (88%, n=22) confined to the pineal gland (72%, n=18), with hormone dysfunction in 24% ( n=6). Only two female pts (8%) have presented with suprasellar and pituitary midline lesions causing headache, progressive visual loss and hypothalamic failure including cranial diabetes insipidus. Eloquent areas in the brain cannot be biopsied so only 60% PICGCTs ( n=15) were confirmed histologically, 47% as germinoma ( n=7), 27% dysgerminoma ( n=4), 27% unclassified ( n=4). Tumour markers (TM) were elevated in all pts with cerebrospinal fluid (CSF) evaluation ( n=5) compared to elevated serum TM in under half (44%, n=12). 68% pts required emergency treatment for a new cancer diagnosis ( n=17): neurosurgery (59%, n=10), chemotherapy (35%, n=6) or radiotherapy (6%, n=1). 88% PICGCT pts received EP-OMB ( n=22) with intrathecal Methotrexate in 63% ( n=14). For all PICGCT pts, 72% pts remain alive ( n=18) with median follow-up 3.8 years (range 0.2-27.3). For 36% pts with TM relapse or radiological progression despite treatment ( n=9), 44.4% remain alive ( n=4) with median overall survival at 6.8 years (range 1.1-18.6). Conclusions: PICGCT pts frequently require emergency surgical treatment for a new cancer diagnosis. Although rare, accurate diagnosis will affect management and prognosis in this young patient group. CSF rather than serum TM analysis is crucial for diagnostic work-up. Consensus on optimal management is warranted given the potential toxicity from multiple therapeutic interventions administered with curative intent.

From the Pineal Gland to the Central Clock in the Brain: Beginning of Studies of the Mammalian Biological Rhythms in the Institute of Physiology of the Czech Academy of Sciences.

The Institute of Physiology of the Czech Academy of Sciences (CAS) has been involved in the field of chronobiology, i.e., in research on temporal regulation of physiological processes, since 1970. The review describes the first 35 years of the research mostly on the effect of light and daylength, i.e., photoperiod, on entrainment or resetting of the pineal rhythm in melatonin production and of intrinsic rhythms in the central biological clock. This clock controls pineal and other circadian rhythms and is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. During the early chronobiological research, many original findings have been reported, e.g. on mechanisms of resetting of the pineal rhythm in melatonin production by short light pulses or by long exposures of animals to light at night, on modulation of the nocturnal melatonin production by the photoperiod or on the presence of high affinity melatonin binding sites in the SCN. The first evidence was given that the photoperiod modulates functional properties of the SCN and hence the SCN not only controls the daily programme of the organism but it may serve also as a calendar measuring the time of a year. During all the years, the chronobiological community has started to talk about "the Czech school of chronobiology". At present, the today´s Laboratory of Biological Rhythms of the Institute of Physiology CAS continues in the chronobiological research and the studies have been extended to the entire circadian timekeeping system in mammals with focus on its ontogenesis, entrainment mechanisms and circadian regulation of physiological functions. Key words: Pineal, Melatonin, AA-NAT rhythm, Light entrainment, Photoperiod, SCN clock.

Interaction of the Melatonin/Ca2+-CaM Complex with Calmodulin Kinase II: Physiological Importance.

Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biologic activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation, where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to different proteins such as calmodulin: a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence supporting that melatonin binds to calmodulin in presence of calcium, and we discuss the effects of this indolamine on the activity of calmodulin kinase II as an inhibitor and as stimulator of calmodulin-dependent protein kinase II activity. We also provide a literature review supporting the relevance of melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient, conserved mechanism. Finally, we highlight the importance of antioxidant effects of melatonin on calmodulin preservation. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of calmodulin kinase II, the possible mechanisms involved, and the relevance on regulation of circadian rhythms and neurodevelopment. Finally, we describe evidence supporting that the binding of melatonin to calmodulin hydrophobic pockets may prevent the oxidation of methionine species with a shielding effect that preserves the functionality of calmodulin.

Potential Neuroprotective Effect of Melatonin in the Hippocampus of Male BTBR Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients, substantial morphological alterations have been observed in the hippocampus, which represents an important region for the development of social skills. Melatonin, commonly found in many foods and plants, is also produced by the pineal gland. This indolamine, known to regulate the circadian rhythm, shows antioxidant and anti-inflammatory properties. We therefore hypothesized that melatonin may reduce oxidative stress and inflammation in the hippocampus of ASD patients. We explored our hypothesis using the BTBR mouse, a well-regarded murine transgenic model for ASD. Immediately after weaning, male BTBR and C57BL/6 mice underwent an 8-week treatment with melatonin or vehicle. Later, through immunohistochemistry and the immunoblotting analysis of the hippocampus, we evaluated the overall expression and cellular localization of Nrf2 and SOD1, two enzymes involved in the oxidative stress response. Similarly, we evaluated NLRP3 and NFkB, two mediators of inflammation, and GAD67, an enzyme responsible for the synthesis of GABA. Ultimately, we addressed melatonin's potential to regulate iron metabolism through a DAB-enhanced Perls reaction assay. Results showed melatonin's potential for modulating the analyzed markers in BTBR mice, suggesting a potential neuroprotective effect in ASD patients.

Effects of Pinealectomy and Melatonin Supplementation on Elements Metabolism in Rat Testicular Tissue

Objective: The aim of this study was to investigate how pinealectomy and melatonin application affect elements metabolism in rat testicular tissue. Methods: The study was carried out on 32 adult male Spraque-Dawley rats. Animals were divided into 4 equal groups. Group 1: Control, Group 2: Melatonin, Group 3: Pinealectomy, Group 4: Pinealectomy+Melatonin. Group 2 and 4 animals received daily 3mg/kg intraperitoneal (ip) melatonin supplementation for 4 weeks. The pineal glands of Group 3 and 4 animals were removed under general anesthesia. At the end of the applications, testicular tissue samples were taken from the animals sacrificed under general anesthesia. Elemental determinations (µg/gram/tissue) were performed in testicular tissue samples using the atomic emission method. Results: The highest cobalt, molybdenum, nickel, manganese, phosphorus, and sodium levels (p<0.001) and the lowest potassium levels in the testicular tissue were obtained in the pinealectomy group (group 3) (p<0.001). Magnesium and selenium values in testicular tissue were highest in the pinealectomy group (group 3) (p<0.001), and were higher in the pinealectomy+melatonin group (group 4) than ingroup 1 (control) and group 2 (melatonin) (p<0.001). Testicular zinc levels were highest in group 2, where melatonin was administered, and lowest in group 3, which was the pinealectomy group (p<0.001). Conclusion: The findings obtained as a result of the study show that pinealectomy significantly disrupts element metabolism in the testicular tissue of rats, and melatonin supplementation may have a regulatory effect on testicular elemental metabolism.

Retinoschisin Is Required for Pineal Gland Calcification and Cellular Communication in Pinealocytes of Rats and Mice

Retinoschisin (RS1) is a secretory protein specifically localized to the extracellular domains in both the lateral retina and the pineal gland (PG). However, the functions of RS1 in the pineal body are poorly understood. To address this knowledge gap, in this study, we undertook histochemical, ultrastructural, and Western blotting analyses of the PG in rats and RS1-knock-in transgenic. We found that RS1 plays a key role in pineal gland calcification (PGC) in mice through both extracellular and intracellular pathways. RS1 was clustered around the cell membrane or intracellularly in pinealocytes, actively participating in the exchange of calcium and thereby mediating PGC. Additionally, RS1 deposition is essential for maintaining PGC architecture in the intercellular space of the adult PG. In RS1-knock-in mice with a nonsense mutation (p.Y65X) in the Rs1-domain of RS1, the Rs1-domain is chaotically dispersed in pinealocytes and the intercellular region of the PG. This prevents RS1 from binding calcified spots and forming calcified nodules, ultimately leading to the accumulation of calcareous lamellae in microvesicles. Additionally, RS1 was observed to colocalize with connexin-36, thereby modulating intercellular communication in the PG of both rats and mice. Our study revealed for the first time that RS1 is essential for maintaining PGC architecture and that it colocalizes with connexin 36 to modulate intercellular communication in the PG. These findings provide novel insights into the function of the RS1 gene in the PG.

Pineal Apoplexy: Highlighting the Causes, Treatment, and Outcome.

Pineal apoplexy, alternatively referred to as pineal hemorrhage or pineal gland hemorrhagic stroke, is an infrequent pathologic condition characterized by bleeding within the pineal gland. In this review, we encompass the primary factors contributing to this uncommon ailment. The retrieval of pertinent research, including patients with pineal apoplexy, was conducted through PubMed, Google Scholar, and Scopus databases. This study exclusively incorporated comprehensive articles written in the English language. The search encompassed the MeSH terms "pineal apoplexy" and "pineal hemorrhage." A total of 41 articles were identified, encompassing a collective sample size of 57 patients. The median age of the patients in the study was 30 years, with a range spanning from 1 to 73 years. There were 27 males, representing 47.4% of the participants. The study identified the most often reported symptoms as headache (49; 86%), nausea/vomiting (19; 33.3%), and Parinaud's syndrome (16; 28.1%). The treatment options encompass several approaches, including open resection, shunting, ventriculostomy, endoscopic aspiration, and conservative care. In the conducted study, a notable number of patients, amounting to 45 cases (78.9%), indicated an amelioration of their symptoms upon their discharge. Data from a cohort of 57 cases provide insights into symptoms, lesions, treatments, and outcomes. Management approaches range from conservative measures to surgical interventions, with prognosis hinged on timely intervention. This investigation serves as a valuable resource for clinicians and researchers, underscoring the need for early diagnosis before permanent neurologic dysfunction happens and tailored treatments for optimal outcomes in pineal apoplexy cases.

Case report on melatonin overdose: Cause and concern

Melatonin, the primary hormone secreted by the pineal gland, regulates central and peripheral oscillators and adapts the internal environment to the external one through MT1 and MT2 receptors. The authors present a case of 16-year-old male intentionally overdosed on 900mg of melatonin (180 tablets) and 10 tablets of 0.5mg alprazolam. Admitted to the emergency department, he was extremely drowsy and minimally responsive with a Glasgow coma scale score of 8/15. Vital signs were stable, and no renal or liver dysfunction was noted. Elevated total leucocyte count and positive benzodiazepine urine test were observed. Gastric lavage was performed, and toxicology reports showed blood alprazolam levels at 0.15 mg/litre eight hours post-overdose. The patient regained consciousness 32 hours post-ingestion and was transferred to the psychiatry unit. This case underscores the increasing abuse of melatonin due to its easy availability and lack of regulation. Although melatonin has a low toxicity potential, side effects and interactions with other drugs can be severe. Supportive measures and vital sign control are crucial in overdose treatment.

Impact of Prenatal LPS and Early-life Constant Light Exposure on Circadian Gene Expression Profiles in Various Rat Tissues

Exposure to lipopolysaccharide (LPS) during prenatal development leads to various changes in neurobiological and behavioural patterns. Similarly, continuous exposure to constant light (LL) during the critical developmental period of the circadian system affects gene expression in various tissues in adulthood. Given the reciprocal nature of the interaction between the circadian and the immune systems, our study primarily investigated the individual effects of both interventions and, more importantly, their combined effect. We aimed to explore whether there might be a potential synergistic effect on circadian rhythms and their parameters, focussing on the expression of clock genes, immune-related genes, and specific genes in the hippocampus, pineal gland, spleen and adrenal gland of rats at postnatal day 30. Our results show a significant influence of prenatal LPS and postnatal LL on the expression profiles of all genes assessed. However, the combination of prenatal LPS and postnatal LL only revealed an enhanced negative effect in a minority of the comparisons. In most cases, it appeared to attenuate the changes induced by the individual interventions, restoring the measured parameters to values closer to those of the control group. In particular, genes such as Nr1d1, Aanat and Tph1 showed increased amplitude in the pineal gland and spleen, while the kynurenine enzymes Kynu and KatII developed circadian rhythmicity in the adrenal glands only after the combined interventions. Our data suggest that a mild immunological challenge during prenatal development may play a critical role in triggering an adaptive response of the circadian clock later in life.

PHARMACOLOGICAL EFFECTS OF MELATONIN AND ITS POTENTIAL APPLICATION IN THERAPY OF GOUT AND ASSOCIATED DISEASES

Introduction. The disturbance in biosynthetic activity of pinealocytes of the pineal gland and subsequent melatonin deficiency in the body are linked to the progression of certain chronic diseases. This has prompted research into correcting chrono-biological dysfunctions, particularly in conditions such as gout and its comorbidities. This study aims to analyze the potential use of melatonin in correcting metabolic disorders in gout and to justify its use as a pharmacotherapeutic agent for treating metabolic and cardiovascular diseases. Materials and methods. We conducted a comprehensive analysis of modern scientific literature from specialized domestic and foreign sources. Emphasis was placed on studies exploring the pharmacological and pharmacotherapeutic aspects of melatonin use in both experimental and clinical settings, particularly those conducted in the last 5-6 years. Results. The research data revealed three main aspects of the problem that must be addressed to understand the experimental, biological, pharmacological, and pharmacotherapeutic foundations for the long-term use of melatonin in clinical practice. The first part of the review highlighted the significant impact of melatonin homeostasis disruption on the pathogenesis of gout and its progression in comorbidity with other conditions such as hypertension, obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The role of chronobiological disorders and desynchronosis in the progression of these diseases was also established. Pharmacological studies demonstrated the pivotal role of melatonin, as an important factor in neuroendocrine regulation, in organizing the circadian rhythm of the body's vital functions under normal and pathological conditions. Melatonin was found to normalize the pathological processes underlying gout development and comorbid diseases, providing a scientific basis for its use in the treatment of gout, cardiovascular diseases, disturbed metabolic processes, and normalization of circadian rhythms in patients with these conditions. Conclusions. This paper presents data on the causes of gout development and progression, as well as some comorbid diseases, from the perspective of chronobiological disruptions in the body's functions. The review sections delve into the pharmacological and pharmacotherapeutic aspects of melatonin's therapeutic action. The findings confirm the importance of melatonin in effectively treating gout and other comorbid diseases and metabolic disorders.

Melatonin ameliorates multiorgan injuries induced by severe acute pancreatitis in mice by regulating the Nrf2 signaling pathway

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.

The potential effect of melatonin on in vitro oocyte maturation and embryo development in animals.

Melatonin is a hormone mainly secreted by the pineal gland during the circadian cycle, with low levels during the daytime and prominent levels during the night. It is involved in numerous physiological functions including the immune system, circadian rhythm, reproduction, fertilization, and embryo development. In addition, melatonin exerts anti-inflammatory and antioxidant effects inside the body by scavenging reactive oxygen and reactive nitrogen species, increasing antioxidant defenses, and blocking the transcription factors of pro-inflammatory cytokines. Its protective activity has been reported to be effective in various reproductive biotechnological processes, including in vitro maturation (IVM), embryo development, and survival rates. In this comprehensive review, our objective is to summarize and debate the potential mechanism and impact of melatonin on oocyte maturation and embryo development through various developmental routes in different mammalian species.

Pineal gland volume loss in females with multiple sclerosis.

Multiple sclerosis has a complex pathophysiology, and numerous risk factors can contribute to its development, like exposure to sunlight that is associated with serum levels of melatonin. The aim of this study was to determine whether the volume of the pineal gland, assessed by magnetic resonance imaging (MRI), correlated with the presence of multiple sclerosis. This retrospective study included a total of 394 patients. Subjects were divided into two groups: the first group consisted of 188 patients with a definite diagnosis of multiple sclerosis (based on revised McDonald criteria) and the second group consisted of 206 healthy controls. To examine the influence of age on pineal gland volume, we stratified the whole sample into three age groups: first involved patients under 20 years, second patients between 20 and 40 years, and third group included patients over 40 years. The maximum length (L) and height (H) of the pineal gland were measured on the T1-weighted sagittal images, and the width (W) was measured on the T2-weighted coronal or axial images. The volume of the gland was calculated as an approximation to an ellipse, according to the formula V = (L × H × W)/2. Pineal gland volume of female multiple sclerosis (MS) patients (N = 129) was significantly lower than in healthy females (N = 123) (p = 0.013; p < 0.05), unlike in males where there is not such difference. Also, pineal gland volume is not age-dependent, and the observed smaller pineal gland in MS patients can reliably be attributed to the disease itself. Additionally, large pineal gland size, especially over 62.83 mm3 when compared to pineal gland volume below 31.85 mm3 is associated with more than double reduced risk of multiple sclerosis (OR 0.42; p = 0.003). Our results suggest that women with multiple sclerosis have smaller pineal glands that can theoretically be explained by a lack of input stimuli and the resultant decrease in gland volume. Additionally, the risk of multiple sclerosis is reduced in larger pineal gland volumes.

Dual sources of melatonin and evidence for different primary functions.

This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells.