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.

[Surgery for Pineal Region Tumors: Concept and Technical Aspects of Occipital Transtentorial Approach].

This article describes the concept and technical aspects of the occipital transtentorial approach(OTA)for tumor extraction in the pineal region, based on the author's experience and literature review. Awareness of the successful completion of each surgical step is essential. Preoperative preparation and imaging evaluations, with particular attention to the veins and venous sinuses, are especially important. It is also helpful to perform a complete dura incision and inversion up to the edge of confluence, superior sagittal sinus, and transverse sinus. Subsequently, it is necessary to understand the usefulness of adequate dissection in the vicinity of the corpus callosum and internal occipital vein(IOV)so that the occipital lobe can be moved without difficulty. Furthermore, development of the IOV with adequate tentoriotomy facilitates contralateral work. Finally, complete understanding of each step during the bilateral, ambient cistern and cerebellomesencephalic fissure dissection process, where the cerebellar vermis can be moved without difficulty, is necessary for a safe OTA to pineal region tumor extraction.

Melatonin in energy control: Circadian time-giver and homeostatic monitor.

Melatonin is a neurohormone synthesized from dietary tryptophan in various organs, including the pineal gland and the retina. In the pineal gland, melatonin is produced at night under the control of the master clock located in the suprachiasmatic nuclei of the hypothalamus. Under physiological conditions, the pineal gland seems to constitute the unique source of circulating melatonin. Melatonin is involved in cellular metabolism in different ways. First, the circadian rhythm of melatonin helps the maintenance of proper internal timing, the disruption of which has deleterious effects on metabolic health. Second, melatonin modulates lipid metabolism, notably through diminished lipogenesis, and it has an antidiabetic effect, at least in several animal models. Third, pharmacological doses of melatonin have antioxidative, free radical-scavenging, and anti-inflammatory properties in various in vitro cellular models. As a result, melatonin can be considered both a circadian time-giver and a homeostatic monitor of cellular metabolism, via multiple mechanisms of action that are not all fully characterized. Aging, circadian disruption, and artificial light at night are conditions combining increased metabolic risks with diminished circulating levels of melatonin. Accordingly, melatonin supplementation could be of potential therapeutic value in the treatment or prevention of metabolic disorders. More clinical trials in controlled conditions are needed, notably taking greater account of circadian rhythmicity.

Optic nerve sheath diameter correlates with both success and failure of hydrocephalus treatment in pediatric patients with pineal region lesions.

BACKGROUND: Pineal region lesions in children are heterogenous pathologies often symptomatic due to occlusive hydrocephalus and thus elevated intracranial pressure (ICP). MRI-derived parameters to assess hydrocephalus are the optic nerve sheath diameter (ONSD) as a surrogate for ICP and the frontal occipital horn ratio (FOHR), representing ventricle volume. As elevated ICP may not always be associated with clinical signs, the adjunct of ONSD could help decision making in patients undergoing treatment. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with pineal region lesions undergoing surgical treatment with respect to pre- and postoperative ONSD and FOHR as an indicator for hydrocephalus. METHODS: Retrospective data analysis was performed in all patients operated for pineal region lesions at a tertiary care center between 2010 and 2023. Only patients with pre- and postoperative MRI were selected for inclusion. Clinical data and ONSD at multiple time points, as well as FOHR were analyzed. Imaging parameter changes were correlated with clinical signs of hydrocephalus before and after surgical treatment. RESULTS: Thirty-three patients with forty operative cases met the inclusion criteria. Age at diagnosis was 10.9 ± 4.6 years (1-17 years). Hydrocephalus was seen in 80% of operative cases preoperatively (n = 32/40). Presence of hydrocephalus was associated with significantly elevated preoperative ONSD (p = 0.006). There was a significant decrease in ONSD immediately (p < 0.001) and at 3 months (p < 0.001) postoperatively. FOHR showed a slightly less pronounced decrease (immediately p = 0.006, 3 months p = 0.003). In patients without hydrocephalus, no significant changes in ONSD were observed (p = 0.369). In 6/6 patients with clinical hydrocephalus treatment failure, ONSD increased, but in 3/6 ONSD was the only discernible MRI change with unchanged FOHR. CONCLUSIONS: ONSD measurements may have utility in evaluating intracranial hypertension due to hydrocephalus in patients with pineal region tumors. ONSD changes appear to have value in assessing hydrocephalus treatment failure.

Homeobox gene-encoded transcription factors in development and mature circadian function of the rodent pineal gland.

Homeobox genes encode transcription factors that are widely known to control developmental processes. This is also the case in the pineal gland, a neuroendocrine brain structure devoted to nighttime synthesis of the hormone melatonin. Thus, in accordance with high prenatal gene expression, knockout studies have identified a specific set of homeobox genes that are essential for development of the pineal gland. However, as a special feature of the pineal gland, homeobox gene expression persists into adulthood, and gene product abundance exhibits 24 h circadian rhythms. Recent lines of evidence show that some homeobox genes even control expression of enzymes catalyzing melatonin synthesis. We here review current knowledge of homeobox genes in the rodent pineal gland and suggest a model for dual functions of homeobox gene-encoded transcription factors in developmental and circadian mature neuroendocrine function.

Effect of Melatonin on Herpesvirus Type 1 Replication.

Acute HSV-1 infection is associated with mild symptoms, such as fever and lesions of the mouth, face and skin. This phase is followed by a latency period before reactivation, which is associated with symptoms ranging from ulcers to encephalitis. Despite available anti-HSV-1 drugs, the development of new antiviral agents is sought due to the presence of resistant viruses. Melatonin, a molecule secreted by the pineal gland, has been shown to be an antioxidant, inducer of antioxidant enzymes, and regulator of various biological processes. Clinical trials have explored its therapeutic utility in conditions including infections. This study focuses on melatonin's role in HSV-1 replication and the underlying mechanisms. Melatonin was found to decrease the synthesis of HSV-1 proteins in infected Vero cells measured by immunofluorescence, indicating an inhibition of HSV-1 replication. Additionally, it regulates the activities of antioxidant enzymes and affects proteasome activity. Melatonin activates the unfolded protein response (UPR) and autophagy and suppresses apoptosis in HSV-1-infected cells. In summary, melatonin demonstrates an inhibitory role in HSV-1 replication by modulating various cellular responses, suggesting its potential utility in the treatment of viral infections.

Role of Melatonin in Viral, Bacterial and Parasitic Infections.

In all mammals, the circulating pool of MLTs is synthesized in the pineal gland during the night's darkness hours. Its main function is synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm or circulate, and plays a detoxifying and cytoprotective role. Circulating MLT may stimulate both innate and acquired immune responses through its circadian action and by activating high-affinity receptors on immunocompetent cells. Extra-pineal MLT may have antioxidant and anti-inflammatory effects that dampen the innate immune response. These two seemingly divergent roles may be considered to be two sides of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effects of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility of integrating the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite of the fact that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.

[Microsurgical ventriculostomy of the third ventricle with access through a burrhole in the treatment of midly located deep-seated brain tumors]. / Mikrokhirurgicheskaya ventrikulostomiya III zheludochka s dostupom cherez frezevoe otverstie v lechenii sredinno raspolozhennykh glubinnykh opukholei golovnogo mozga.

BACKGROUND: Currently, endoscopic third ventriculostomy and simultaneous biopsy of deep midline brain tumors are a generally accepted option in neurooncology. Nevertheless, effectiveness of this surgery and diagnostic accuracy of biopsy are not without drawbacks. An alternative to endoscopic surgery may be simultaneous microsurgical third ventriculostomy and biopsy of deep midline tumors. OBJECTIVE: To evaluate effectiveness and safety of burr hole microsurgical third ventriculostomy in the treatment of deep midline brain tumors. MATERIAL AND METHODS: We used transcortical (25 cases) and transcallosal (8 cases) approaches for microsurgical third ventriculostomy. RESULTS: Initially scheduled biopsy was performed in 19 cases, partial resection in 6 cases, subtotal resection in 4 cases and total resection in 4 cases. All patients underwent microsurgical third ventriculostomy. In 12 cases, stenting of stoma was performed in addition to ventriculostomy. Biopsy was informative in all cases. Postoperative follow-up period ranged from 3 to 44 months (mean 29 months). There was no postoperative hydrocephalus and need for shunting procedure. CONCLUSION: Burr hole microsurgery may be an alternative to endoscopic surgery for the treatment of pineal, periaqueductal and third ventricular tumors.

Autonomic dysfunction in patients with tectal plate compression: A systematic review.

INTRODUCTION: Pineal region lesions can result in tectal plate compression, hydrocephalus, and associated symptoms including headache, Parinaud's Syndrome, and epileptic phenomena. No studies have looked at the relationship between these lesions and the autonomic nervous system. METHODS: To evaluate the clinical presentation of pineal lesions secondary to tectal plate compression with a focus on autonomic dysfunction, a systematic review was completed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Case reports and prospective and retrospective studies on patients with pineal or tectal region lesions were included. RESULTS: Of 73 identified studies, 43 underwent full text screening. 26 studies (n=363 patients; age range 0-69 years) were included. 47.1% of patients were male (n=171). Obstructive hydrocephalus was identified in 119 patients (32.8%). The most common symptom was headache (n=228, 62.8%), followed by epileptic phenomena (n=76, 20.9%). Vision related symptoms were identified in 88 patients (24.2%). 251 patients (69.1%) had symptoms associated with autonomic dysfunction including dizziness, nausea, pupillary dysfunction, photophobia and fatigue. Of the 200 (55%) patients who underwent surgery, 135 patients (67.5%) had improved or resolved symptoms post-operatively, including 120 patients with improved autonomic dysfunction symptoms. CONCLUSIONS: Though these lesions are most characterized by Parinaud's syndrome and hydrocephalus, this review suggests dysfunction of the autonomic nervous system may be at play and require consideration at initial presentation and treatment.

Circadian patterns and photoperiodic modulation of clock gene expression and neuroendocrine hormone secretion in the marine teleost Larimichthys crocea.

The light/dark cycle, known as the photoperiod, plays a crucial role in influencing various physiological activities in fish, such as growth, feeding and reproduction. However, the underlying mechanisms of this influence are not fully understood. This study focuses on exploring the impact of different light regimes (LD: 12 h of light and 12 h of darkness; LL: 24 h of light and 0 h of darkness; DD: 0 h of light and 24 h of darkness) on the expression of clock genes (LcClocka, LcClockb, LcBmal, LcPer1, LcPer2) and the secretion of hormones (melatonin, GnRH, NPY) in the large yellow croaker, Larimichthys crocea. Real-time quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assays were utilized to assess how photoperiod variations affect clock gene expression and hormone secretion. The results indicate that changes in photoperiod can disrupt the rhythmic patterns of clock genes, leading to phase shifts and decreased expression. Particularly under LL conditions, the pineal LcClocka, LcBmal and LcPer1 genes lose their rhythmicity, while LcClockb and LcPer2 genes exhibit phase shifts, highlighting the importance of dark phase entrainment for maintaining rhythmicity. Additionally, altered photoperiod affects the neuroendocrine system of L. crocea. In comparison to the LD condition, LL and DD treatments showed a phase delay of GnRH secretion and an acceleration of NPY synthesis. These findings provide valuable insights into the regulatory patterns of circadian rhythms in fish and may contribute to optimizing the light environment in the L. crocea farming industry.

The first pineoblastoma case report of a patient with Sotos syndrome harboring NSD1 germline mutation.

Germline mutations of NSD1 are associated with Sotos syndrome, characterized by distinctive facial features, overgrowth, and developmental delay. Approximately 3% of individuals with Sotos syndrome develop tumors. In this study, we describe an infant in pineoblastoma with facial anomalies, learning disability and mild autism at 1 years diagnosed as Sotos syndrome owing to carrying a novel mutation de novo germline NSD1 likely pathogenic variant. This patient expands both the mutation and phenotype spectrum of the Sotos Syndrome and provides new clinical insights into the potential mechanism of underlying pinealoblastoma pathology.

Constant light and pinealectomy disrupt daily rhythm in song production and negatively impact reproductive performance in zebra finches.

We assessed the circadian clock control of singing and reproductive performance in zebra finches. Experiment 1 examined changes in body mass, testis size, and plasma corticosterone and testosterone levels in male birds exposed to constant light (LL, 100 lx) and constant darkness (DD, 0.5 lx), with controls on 12L:12D (L = 100 lx, D = 0.5 lx). There was a significant increase in the body mass and testis size under LL and a decrease in testis size under the DD. Using a similar design, experiment 2 assessed the persistence of the circadian rhythm in singing along with activity-rest pattern in cohort I birds that were entrained to 12L:12D and subsequently released in DD or LL, and in cohort II birds that were entrained to 12L:12D and following pinealectomy were released in DD. Both activity and singing patterns were synchronized with the light phase under 12L:12D, free-ran with a circadian period under DD, and were arrhythmic under the LL. There was an overall decreased and increased effect on singing under DD and LL, respectively, albeit with differences in various song parameters. The pinealectomy disrupted both activity and singing rhythms but did not affect singing or the overall song features. Pinealectomized bird pairs also exhibited a significant reduction in their nest-building and breeding efforts, resulting in a compromised reproductive performance. These results suggest a circadian clock control of singing and more importantly demonstrate a role of the pineal clock in breeding behaviors, leading to a compromised reproductive performance in diurnal zebra finches.

[Neurosurgical treatment of tumors of the pineal region - literature review and overview of cases at OMIII]. / A pineális régió tumorainak idegsebészeti ellátása ­ irodalmi áttekintés és az OMIII beteganyagának vizsgálata.

Pineal region tumors account for less than 1% of adult supratentorial tumors. Their treatment requires a multimodality approach. Previously, the treatment of choice was direct surgery, which is associated with high surgical risk. Advances in minimally invasive techniques and onco-radiotherapy offer a safe and multimodal personalized therapy. The aim of our study was to describe the practice of our Institute based on combined endoscopic and radiotherapy techniques. We performed a retrospective clinical study. We processed data from 23 adult patients who underwent endoscopic third ventricle fenestration and pineal tumor biopsy between 2014 and 2023. Descriptive statistics, t-test, Fisher's exact test and Kaplan-Meier analysis were performed. Clinical improvement with endoscopic intervention was achieved in 78.3% of cases. Significant increase in preoperative performance status was observed in the postoperative period (p=2.755e-5), and radiotherapy resulted in regression or stable disease. Our results suggest a safe treatment with good clinical outcome and an excellent alternative to direct surgery.

The role of melatonin deficiency induced by pinealectomy on motor activity and anxiety responses in young adult, middle-aged and old rats.

BACKGROUND: Aging affects anxiety levels in rats while the pineal gland, via its hormone melatonin, could modulate their inherited life "clock." The present study aimed to explore the impact of plasma melatonin deficiency on anxiety responses and the possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) axis and heat shock proteins (Hsp) 70 and 90 in the frontal cortex (FC) and the hippocampus in young adult, middle-aged and elderly rats with pinealectomy. RESULTS: Melatonin deficiency induced at different life stages did not affect the lifespan of rats. Pinealectomy abolished the circadian rhythm of motor activity, measured for 48 h in the actimeter, in young adult but not in middle-aged rats. Pinealectomy reduced the motor activity of the young adult rats during the dark phase and impaired the diurnal activity variations of old rats. The same generations (3- and 18 month-old rats with pinealectomy) had lower anxiety levels than the matched sham groups, measured in three tests: elevated-plus maze, light-dark test, and novelty-suppressed feeding test. While the activity of the HPA axis remained intact in young adult and middle-aged rats with melatonin deficiency, a high baseline corticosterone level and blunted stress-induced mechanism of its release were detected in the oldest rats. Age-associated reduced Hsp 70 and 90 levels in the FC but not in the hippocampus were detected. Pinealectomy diminished the expression of Hsp 70 in the FC of middle-aged rats compared to the matched sham rats. CONCLUSIONS: Our results suggest that while melatonin hormonal dysfunction impaired the motor activity in the actimeter and emotional behavior in young adult and elderly rats, the underlying pathogenic mechanism in these generations might be different and needs further verification.

Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish.

The eye is instrumental for controlling circadian rhythms in mice and human. Here, we address the conservation of this function in the zebrafish, a diurnal vertebrate. Using lakritz (lak) mutant larvae, which lack retinal ganglion cells (RGCs), we show that while a functional eye contributes to masking, it is largely dispensable for the establishment of circadian rhythms of locomotor activity. Furthermore, the eye is dispensable for the induction of a phase delay following a pulse of white light at CT 16 but contributes to the induction of a phase advance upon a pulse of white light at CT21. Melanopsin photopigments are important mediators of photoentrainment, as shown in nocturnal mammals. One of the zebrafish melanopsin genes, opn4xa, is expressed in RGCs but also in photosensitive projection neurons in the pineal gland. Pineal opn4xa+ projection neurons function in a LIGHT ON manner in contrast to other projection neurons which function in a LIGHT OFF mode. We generated an opn4xa mutant in which the pineal LIGHT ON response is impaired. This mutation has no effect on masking and circadian rhythms of locomotor activity, or for the induction of phase shifts, but slightly modifies period length when larvae are subjected to constant light. Finally, analysis of opn4xa;lak double mutant larvae did not reveal redundancy between the function of the eye and opn4xa in the pineal for the control of phase shifts after light pulses. Our results support the idea that the eye is not the sole mediator of light influences on circadian rhythms of locomotor activity and highlight differences in the circadian system and photoentrainment of behaviour between different animal models.

Microsurgical Resection of a Pineal Cyst via a Paramedian Supracerebellar Infratentorial Approach.

Pineal cysts are typically detected in around 1.3% to 4.3% of patients during routine magnetic resonance imaging (MRI) scans.1,2 The vast majority of pineal cysts are benign, asymptomatic, and typically do not necessitate surgical intervention. Large pineal cysts are known to cause hydrocephalus with its associated symptoms and thus can require in rare cases surgical resection. Even in the absence of hydrocephalus, selected patients with large pineal cysts causing headaches and visual disturbances can find relief after surgical resection.3,4 The supracerebellar infratentorial (SCIT) approach is widely used and represents an extraparenchymatous approach through a natural corridor to the pineal region.5 Performing this approach in a semisitting position allows for an optimal retraction of the cerebellum by gravity. We employ a minimally invasive paramedian SCIT approach for the resection of pineal cysts. In our experience, the paramedian SCIT approach allows for a less steep operating angle and a smaller craniotomy compared with the midline SCIT approach. We present a 24-year-old female complaining of headache. The initial MRI was conducted 2 years before surgery. Following the initial evaluation, the patient experienced progressive headaches without neurologic deficits. A subsequent MRI revealed enlargement of the pineal cyst, leading to the indication for surgical resection. The surgery was performed mainly under the operating microscope with endoscopic visualization in suitable situations as our small approach restricts bimanual dissection with an endoscope. In our experience, this approach provides a versatile and minimally invasive access to the pineal region, making it optimally suitable for pineal cysts requiring surgical resection.

Cytological diagnosis of pineoblastoma in cerebrospinal fluid.

A rare case of pineoblastoma on cerebrospinal fluid cytology was reported in a 15-year-old girl. In the current paper, a rare case of pienoblastoma on CSF cytology has been described.