Pineal Research Articles

Development of RP-HPLC methods for the analysis of melatonin alone and in combination with sleep-enhancing dietary supplements

Melatonin, a hormone produced by the pineal gland, is widely recognized for its role in regulating sleep-wake cycles. With the increasing prevalence of sleep disorders, melatonin supplements have gained popularity as a natural remedy. Additionally, various sleep-enhancing dietary supplements combine melatonin with other active ingredients to enhance efficacy. Reliable and accurate analytical methods are essential for ensuring the quality, safety, and efficacy of these products. Reverse-phase high-performance liquid chromatography (RP-HPLC) is a powerful analytical technique widely used for the separation, identification, and quantification of compounds in complex mixtures. This article explores the development and validation of RP-HPLC methods for the analysis of melatonin, both as a single ingredient and in combination with other components in sleep-enhancing dietary supplements.

Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis

ABSTRACTDiabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial–mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA‐sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co‐immunoprecipitation (co‐IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

Role of Melatonin in Periodontal Diseases: A Structured Review.

Melatonin is produced by the pineal gland and plays a role in regulating circadian rhythm. It influences the physiologic processes, such as the activation of the immune system and the antioxidant function. Melatonin has been reported in the samples of patients with periodontitis. Therefore, the role of melatonin in periodontal diseases must be appraised. Using the strategy of electronic search of various databases, we included studies, published until December 2021, measuring the expression of melatonin in patient samples and evaluating the effect of periodontal therapy on melatonin expression. This review also included studies evaluating the effect of melatonin supplementation on periodontal parameters. In total, 15 articles fulfilled the study inclusion criteria. The results revealed that melatonin is negatively correlated with the severity of periodontal diseases, and melatonin supplementation reduces the levels of periodontal inflammatory parameters. Hence, melatonin has a role in periodontal diseases, but additional studies are warranted to substantiate its use as a biomarker and host modulatory agent.

Melatonin partially rescues defects induced by tranexamic acid exposure during oocyte maturation in mice.

Tranexamic acid (TXA) is widely used among young women because of its ability to whiten skin and treat menorrhagia. Nevertheless, its potential effects on oocyte maturation and quality have not yet been clearly clarified. Melatonin (MT) is an endogenous hormone released by the pineal gland and believed to protect cells from oxidative stress injury. In the present study, we used an in vitro maturation model to investigate the toxicity of TXA and the protective role of MT in mouse oocytes. Compared with the control group, the TXA-exposed group had significantly lower nuclear maturation (57.72% vs. 94.08%, P < 0.001) and early embryo cleavage rates (38.18% vs. 87.66%, P < 0.001). Further study showed that spindle organization (52.56% vs. 18.77%, P < 0.01) and chromosome alignment (33.23% vs. 16.66%, P < 0.01) were also disrupted after TXA treatment. Mechanistically, we have demonstrated that TXA induced early apoptosis of oocytes (P < 0.001) by raising the level of reactive oxygen species (P < 0.001), which was consistent with an increase in mitochondrial damage (P < 0.01). Fortunately, all these effects except the spindle defect were successfully rescued by an appropriate level of MT. Collectively, our findings indicate that MT could partially reverse TXA-induced oocyte quality deterioration in mice by effectively improving mitochondrial function and reducing oxidative stress-mediated apoptosis.NEW & NOTEWORTHY Tranexamic acid is increasingly used to whiten skin, reverse dermal damages, and treat heavy menstrual bleeding in young women. However, its potential toxicity in mammalian oocytes is still unclear. Our study revealed that tranexamic acid exposure impaired the mouse oocyte quality and subsequent embryo development. Meanwhile, melatonin has been found to exert beneficial effects in reducing tranexamic acid-induced mitochondrial dysfunction and oxidative stress.

Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway.

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.

Melatonin prevents histopathologies stem from cadmium chloride in pregnant mice lungs.

Heavy metals may cause structural and functional changes in organs. Cadmium, taken into the body through oral and respiratory routes, can lead to lesions. Cadmium may lead to lesions by accumulating in organs. The lungs are significantly affected by cadmium. Melatonin, an antioxidant hormone with therapeutic effects, is secreted by the pineal gland. The aim of the study is to treat cadmium-induced lesions in the lungs of pregnant mice with Melatonin. Four groups were created with 24 pregnant mice, named Control, Cadmium Chloride, Melatonin, and Melatonin + Cadmium Chloride groups (n: 6) Cadmium Chloride (2mg/kg/bw) and Melatonin (3mg/kg/bw) were given orally through gavage during pregnancy (21 days) After routine histological procedures, the lung tissues were stained with Hematoxylin-Eosin and evaluated under a light and electron microscope. ANOVA tests were applied for one-way analysis of variance, and LSD tests were applied for pairwise comparisons (p < 0.05) The average lung weight decreased in the Cadmium Chloride group (p: 0.03) The average lung weight in the Cadmium Chloride + Melatonin group was found to be close to the control group (p: 0.06) Cadmium Chloride caused thickening of the lung alveolar wall, inflammatory cell infiltration, and fibrin deposition. Because the lesions were not observed in the Melatonin group, lesions may be prevented by melatonin. Additional studies may be useful to determine the protective effect of Melatonin at different doses of Cadmium Chloride.

PINEAL GLAND: HISTORICAL EXCURSION AND CURRENT SCIENTIFIC FACTS (LITERATURE REVIEW)

The purpose of the study – to analyze literature data regarding the history of the doctrine formation of the structure and function of the pineal gland. Conclusions. 1. Analysis of the evolution of views on the role of the pineal gland in the regulation of body functions demonstrates that the gland has been a constant subject of scientific discussions and philosophical concepts for several centuries. 2. Modern scientific achievements in the study of the biological effects of the products of the gland’s secretory activity testify to the polydromy of their effects and leave no doubt about the significant prospects in the discovery of new mechanisms of their action.

Melatonin rescues pregnant female mice and their juvenile offspring from high fat diet-induced alzheimer disease neuropathy

High fat diet (HFD) is a prime factor, which contributes to the present epidemic of metabolic syndrome. Prolonged intake of HFD induces oxidative stress (OS) that in turn causes neuroinflammation, neurodegeneration, insulin resistance, amyloid burden, synaptic dysfunction and cognitive impairment hence leading to Alzheimer's disease neuropathy. Melatonin (secreted by the Pineal gland) has the potential to nullify the toxic effects of reactive oxygen species (ROS) and have been shown to ameliorate various complications induced by HFD in rodent models. This study aimed to assess the neurotherapeutic effects of melatonin on HFD-induced neuroinflammation and neurodegeneration mediated by OS in pregnant female mice and their offspring. Western blotting, immunohistochemistry and antioxidant enzyme assays were used for quantification of samples from the hippocampal region of the brain of pregnant albino mice and their offspring. Short- and long-term memory was assessed by Y-maze and Morris Water Maze tests. HFD significantly induced OS leading to AD like neuropathology in the pregnant mice and their offspring while melatonin administration simultaneously with the HFD significantly prevented this neuropathy. This study reports that melatonin exerts these effects through the stimulation of SIRT1/Nrf2/HO-1 pathway that in turn reduces the HFD-induced OS and its downstream signaling. In conclusion melatonin prevents HFD-induced multiple complications that ultimately leads to the memory dysfunction in pregnant female mice and their successive generation via activation of SIRT1/Nrf2 signaling pathway.

Blunted Melatonin Circadian Rhythm in Parkinson's Disease: Express Bewilderment.

Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD.

Intracranial calcifications in Post-mortem Computed Tomography and its forensic implications

ABSTRACT Intracranial physiological calcifications are usually seen in Post-mortem Computed Tomography (PMCT) and are difficult to note with naked-eye examination during conventional autopsy. Studies on intracerebral calcifications in PMCT are few. Moreover, such studies may be of interest from the clinical perspective in order to compare physiological and pathological intracranial calcifications. Hence, the authors aimed to calculate the incidence of calcification of the pineal gland and choroid plexus in the lateral ventricle in brain PMCT and its association with age, sex, type of death, and manner of death. The authors studied 620 PMCT head scans of the deceased whose ages ranged from 2 months to 97 years (mean ± SD is 38.83 ± 15.91). A total of 59.68% had pineal calcification, and 47.42% had choroid plexus calcification with a male preponderance. A statistically significant association was present between the studied calcifications and age, sex, type of death, and manner of death. The calcification was higher in the pineal gland than in the choroid plexus until the fifth decade, and post fifth decade the choroid plexus calcification was more common. The presence of calcification was higher among the suicidal deaths when compared with the non-suicidal deaths with a statistically significant association (p < 0.05).

A Complex Interplay Between Melatonin and RORβ: RORβ is Unlikely a Putative Receptor for Melatonin as Revealed by Biophysical Assays.

A nuclear retinoic acid receptor (RAR)-related orphan receptor β (RORβ) is strictly expressed in the brain, particularly in the pineal gland where melatonin is primarily synthesized and concentrated. The controversial issues regarding the direct interaction of melatonin toward ROR receptors have prompted us to investigate the potential melatonin binding sites on different ROR isoforms. We adopted computational and biophysical approaches to investigate the potential of melatonin as the ligand for RORs, in particular RORβ. Herein, possible melatonin binding sites were predicted by molecular docking on human RORs. The results showed that melatonin might be able to bind within the ligand-binding domain (LBD) of all RORs, despite their difference in sequence homology. The predicted melatonin binding scores were comparable to binding energies with respect to those of melatonin interaction to the well-characterized membrane receptors, MT1 and MT2. Although the computational analyses suggested the binding potential of melatonin to the LBD of RORβ, biophysical validation failed to confirm the binding. Melatonin was unable to alter the stability of human RORβ as shown by the unaltered melting temperatures upon melatonin administration in differential scanning fluorometry (DSF). A thermodynamic isothermal titration calorimetry (ITC) profile showed that melatonin did not interact with human RORβ in solutions, even in the presence of SRC-1 co-activator peptide. Although the direct interaction between the LBD of RORβ could not be established, RORα and RORβ gene expressions were increased upon 24h treatment with μM-range melatonin. Our data, thus, support the studies that the nuclear effects of melatonin may not be directly mediated via its interaction with the RORβ. These findings warrant further investigation on how melatonin interacts with ROR signaling and urge the melatonin research community for a paradigm shift in the direct interaction of melatonin toward RORs. The quest to identify nuclear receptors for melatonin in neuronal cells remains valid for the community to achieve.

Exploration of the white matter bundles connected to the pineal gland: A DTI study.

Pineal gland (PG) is a structure located in the midline of the brain, and is considered as a main part of the epithalamus. There are reports on the role of this area for brain function by hormone secretion, as well as few reports on its role in brain cognition. However, little knowledge is available on the PG, and in particular on the structural connectivity of this region with the other brain structures. Using diffusion-weighted images collected by a 3T MRI scanner, and using a sample of 61 (29F) mentally and physically healthy young individuals in the age range of 20-30 years old, we tried to extract the white matter bundles connected to the PG. Based on prior knowledge, seven target bundles were suggested to be between the PG body and the PG roots, Pons, Periventricular region, thalamus, caudate, lentiform, suprachiasmatic nuclei, and the supercervical ganglia. Nearly all the target bundles were successfully extracted, with the exception of the lentiform. Rate of identification of the tracts was different, with the bundle between the PG body and roots having the highest identification rate (97%); then it was with the Pons (70%), Periventricular region (57%), SCN (55%), left thalamus (52%), right thalamus (47%), left caudate (27%) and right caudate (22%). This study is an attempt to expand our knowledge on the neuroanatomy of the PG, which might help for identifying further roles for it in brain functionality, and also be a help for the treatment of some disorders in the future.

Investigation of the therapeutic effect of melatonin on deltamethrin applied mouse primary hepatocyte culture

Objective In recent years, it has been known that the melatonin hormone, secreted from the pineal gland, possesses significant antioxidant activity. This study explores the therapeutic effect of melatonin on the deleterious effects of deltamethrin, a pyrethroid pesticide extensively used worldwide, including in Türkiye, on mouse liver cells. Methods Hepatocytes from Balb/C mice were isolated using a two-stage perfusion method, resulting in over 85% live hepatocytes. The isolated cells were cultured with different doses of deltamethrin (1 and 10 µM) and melatonin (100 µM) for 24 and 48 hours. At the conclusion of the culture period, hepatocytes were extracted at the 24th and 48th hours, and Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), Total Oxidation Status (TOS), and DNA damages (8-hydroxy-2’-deoxyguanosine (8-OHdG)) were examined. Results While an increase in MDA, TOS, and DNA damage was observed in the deltamethrin-administered groups of hepatocytes, a decrease in TAC level was noted. It was determined that the applied deltamethrin had no effect on cell viability throughout the application period. Conclusion Furthermore, it was observed that melatonin, when administered concurrently with deltamethrin, reduced the toxic effect of deltamethrin. This study suggests that melatonin has a protective effect against deltamethrin-induced damage in mouse hepatocyte cells.

Melatonin and Seasonal Synchrony in Mammals.

In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the pars tuberalis-tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)-related peptide-3 (RFRP-3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization.

AB085. Trans-cortical trans-ventricular approach to pineal tumors: a case series.

Attributing to its deep-seated location, surrounded by significant vessels, surgical management of pineal gland lesions is still considered a challenge. Various surgical approaches are employed to access these lesions, based on patient-specific risks and benefits. Each approach has its merits and demerits. In this study, we aim to narrate our experience with trans-cortical trans-ventricular (TT) approach for pineal tumor resection. We aim to outline the procedure details, safety, efficacy, and treatment outcome of TT. This is a single-center, consecutive case series. All patients with pineal gland tumors who underwent surgical intervention, namely biopsy or resection using TT approach from 2000 to 2023 were included. Data for the patient characteristics, intraoperative details and complications were collected from the hospital's database. Mean [standard deviation (SD)] and frequency (proportions) were calculated for continuous and discrete variables, respectively. We identified 13 patients, mean age 24 (SD: 13) years in our case series. Of them, 8 (61.5%) were male. Most common presenting complains were headaches (69%), nausea/vomiting (38.5%), seizure (23%), and visual deficit (23%). Most patients, 60%, had high grade tumor and average size of tumors were 43.5 mm (SD: 18.45 mm). Pilocytic astrocyotma (23%) and pineal parenchymal tumor of intermediate differentiation (23%) were the most common diagnoses. In total, nine patients had pineal gland lesion biopsy done using TT approach along with the cerebrospinal fluid (CSF) diversion. Of them, four had tumor resection done using the same approach. Whereas four patients had primary excision done using TT approach. There were no intra-operative complications. Two patients had post-operative seizures which were treated with anti-epileptics. We did not identify any long-term sequalae attributed to this approach. We presented our data regarding the safety, efficacy, and outcomes of trans-cortical trans-ventricular approach for pineal tumor surgical management. Utilizing this novel approach for pineal lesion resection can be a great addition to surgeons' armamentarium. This unique approach allows to access the tumor for biopsy/resection and perform CSF diversion procedure, simultaneously. Moreover, the same incision can be used for the second/redo surgery.

Bioactive Peptides in Dairy Milk: Highlighting the Role of Melatonin.

Melatonin, an endogenous indolamine derived from tryptophan, is primarily synthesized by the pineal gland in mammals and regulated by a complex neural system. Its release follows a circadian rhythm, which is crucial for regulating physiological processes in response to light-dark cycles in both humans and animals. In this review, we report that the presence of this hormone in bovine milk, with significant differences in concentration between daytime and nighttime milking, has increased interest in milk as a natural source of bioactive molecules. Melatonin lowers cortisol levels at night, reduces body temperature and blood pressure, coinciding with decreased alertness and performance, acts as an antioxidant and anti-inflammatory agent, modulates the immune system, offers neuroprotective benefits, and supports gastrointestinal health by scavenging free radicals and reducing oxidative stress in dairy cows. Many factors influence the release of melatonin, such as the intensity of artificial lighting during nighttime milking, the frequency of milkings, milk yield, and genetic differences between animals. Nocturnal milking under low-intensity light boosts melatonin, potentially reducing oxidative damage and mastitis risk. Additionally, ultra-high temperature (UHT) treatment does not significantly affect the melatonin content in milk. However, further research on its stability during milk processing and storage is crucial for ensuring product efficacy. In some countries, nighttime milk with naturally elevated melatonin content is already commercialized as a natural aid for sleep. Thus, naturally melatonin-rich milk may be a promising alternative to synthetic supplements for promoting better sleep and overall well-being.

Mouse Models in Circadian Rhythm and Melatonin Research.

This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.

A new species of the Amolops monticola group (Anura, Ranidae) from southern Yunnan, China

A new species of the Amolops monticola group is described from Yunnan Huanglianshan National Nature Reserve, southern Yunnan, China. Morphologically, the new species is characterized by a moderate body size (snout–vent length 38.3–40.8 mm in adult males and 62.3–63.1 mm in adult females), head being longer than wide, nostril to snout tip distance being slightly smaller than eye to nostril distance, the presence of pineal body, distinct tympanum, vomerine teeth being invisible in males and weak but visible in females, distinct dorsolateral folds, the absence of outer metatarsal tubercle, the presence of vocal sac and nuptial pad in adult males, dorsal surface of head and body being green with no or a few black dots, and the presence of a few large flat white tubercles on the posterior inferior flank. Genetically, the uncorrected genetic distance between the new species and other species of the A. monticola group ranged from 3.0% to 7.6% in 16S ribosomal RNA and from 7.2% to 17.1% in NADH dehydrogenase subunit 2 gene sequences. Currently, the new species is known only from its type locality in Lvchun County, Honghe Prefecture, Yunnan Province, China.

Participation of Ca2+-Calmodulin-Dependent Protein Kinase II in the Antidepressant-Like Effects of Melatonin.

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII's role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.

The Pineal Gland, A Bridge Between the Hormonal Perspective and Spiritual Mysticism

The pineal gland has a hormonal and mystical component, described since time immemorial; its main secretion product with recognized health effects is melatonin, which is involved in the light/dark phenomenon. Additionally, this gland has been related to spiritual aspects and divine connection; in fact, for certain traditions, they define it as the “Third Eye” and establish it as the link between the “Body and Mind”. This review describes the most relevant aspects of the functioning of the pineal gland (from a hormonal point of view) and its possible role from a mystical-spiritual point of view.