Fluoride and Pineal Gland

MiR-375-3p mediates reduced pineal function in hypoxia-ischemia brain damage

Although the role of melatonin in many biological functions, foremost among them the regulation of circadian rhythms and sleep, has been widely demonstrated, the definition of a specific disorder linked to melatonin deficiency remains debated. As the main function of the pineal gland is to secrete melatonin, pineal lesions and pinealectomy provide insightful models for understanding the effect of acute and chronic suppression of melatonin secretion ("pinealoprive syndrome"). In pineal parenchymal cell tumor, melatonin levels are usually normal/high, whereas impaired secretion is thought to reflect parenchymal destruction and thus tumors with malignant profiles. Following pinealectomy, low or undetectable levels of melatonin are observed, suggesting that melatonin assay may be used to monitor complete tumoral and pineal gland resection. However, the link between melatonin depletion in this context and the objective/subjective quality of sleep remains unclear. Likewise, while melatonin is involved in a large number of physiological functions, damage to the pineal gland does not appear to have any clear extra-neurological effects. This paradox might be explained by the presence of extra-pineal melatonin secretion sites. In addition, it is possible that the effects of melatonin depletion are long term, in real-life situations, and fluctuate according to the season. Importantly, most evidence relies on very small samples due to the rarity of pineal gland lesions. Further prospective longitudinal studies on wider cohorts are needed, to definitively conclude on the impact of pineal gland-related melatonin on health in general and sleep in particular. There is therefore no recommendation for melatonin supplementation after pinealectomy. Pragmatically, in the presence of melatonin deficiency and sleep disorders in the context of pineal gland tumor/pinealectomy, and given the safety of melatonin as a medication, it seems reasonable to propose exogenous melatonin, with a chronobiotic or sedative purpose depending on the type of disorder.

The pineal gland contains many peptides known to be implicated in melatonin production. We examined the effects of a synthetic pineal tetrapeptide Ala-Glu-Asp-Gly on melatonin secretion by the pineal gland. The tetrapeptide effects on pineal gland melatonin secretion were studied in young (9 weeks) and old (27 months) male Wistar rats using a perifusion device. Pineal tetrapeptide at the concentrations used (10(-4) to 10(-6) M) had no significant effect upon melatonin secretion whatever the age of the animals, young or old. We also looked at the effect of the tetrapeptide on pineal melatonin stimulated by a beta-adrenergic agonist, isoproterenol. We found that isoproterenol-induced melatonin increase was not modified by the tetrapeptide. Our results suggest that the pineal tetrapeptide Ala-Glu-Asp-Gly, does not seem to play a role, at least in vitro, in the control of melatonin secretion by the rat pineal gland.

Melatonin secretion from goldfish pineal gland in organ culture

The modulatory effect of substance P on rat pineal norepinephrine release and melatonin secretion

Psychoactive drugs, pineal gland and affective disorders

Melatonin is synthesized in and secreted from the pineal glands and regulates circadian rhythms. Although melatonin has been reported to modulate the activity of ion channels in several tissues, its effects on pineal ion channels remain unclear. In the present study, the effects of melatonin on voltage-gated K+ (KV) channels, which play a role in regulating the resting membrane potential, were examined in rat pinealocytes. The application of melatonin reduced pineal KV currents in a concentration-dependent manner (IC50 = 309 µM). An expression analysis revealed that KV4.2 channels were highly expressed in rat pineal glands. Melatonin-sensitive currents were abolished by the small interfering RNA knockdown of KV4.2 channels in rat pinealocytes. In human embryonic kidney 293 (HEK293) cells expressing KV4.2 channels, melatonin decreased outward currents (IC50 = 479 µM). Inhibitory effects were mediated by a shift in the voltage dependence of steady-state inactivation in a hyperpolarizing direction. This inhibition was observed even in the presence of 100 nM luzindole, an antagonist of melatonin receptors. Melatonin also blocked the activity of KV4.3, KV1.1, and KV1.5 channels in reconstituted HEK293 cells. The application of 1 mM melatonin caused membrane depolarization in rat pinealocytes. Furthermore, KV4.2 channel inhibition by 5 mM 4-aminopyridine attenuated melatonin secretion induced by 1 µM noradrenaline in rat pineal glands. These results strongly suggest that melatonin directly inhibited KV4.2 channels and caused membrane depolarization in pinealocytes, resulting in a decrease in melatonin secretion through parasympathetic signaling pathway. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands. NEW & NOTEWORTHY Melatonin is a hormone that is synthesized in and secreted from the pineal glands, which regulates circadian rhythms. However, the effects of melatonin on pineal ion channels remain unclear. The present study demonstrated that melatonin directly inhibited voltage-gated potassium KV4.2 channels, which are highly expressed in rat pinealocytes, and induced membrane depolarization, resulting in a decrease in melatonin secretion. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands.

The avian pineal gland, apart from the hypothalamic master clock (suprachiasmatic nuclei, SCN) and retina, functions as an independent circadian oscillator, receiving external photic cues that it translates into the rhythmical synthesis of melatonin, a biochemical signal of darkness. Functional similarity to the mammalian SCN makes the avian pineal gland a convenient model for studies on biological clock mechanisms in general. Pineal melatonin is produced not only in a light-dependent manner but also remains under the control of the endogenous oscillator, while the possible involvement of melatonin in maintaining cyclic expression of the avian clock genes remains to be elucidated. The aim of the present study was to characterize the diurnal profiles of main clock genes transcription in the pineal glands of chickens exposed to continuous light (LL) and supplemented with exogenous melatonin. We hypothesized that rearing chickens from the day of hatch under LL conditions would evoke a functional pinealectomy, influencing, in turn, pineal clock function. To verify this hypothesis, we examined the diurnal transcriptional profiles of selected clock genes as well as the essential parameters of pineal gland function: transcription of the genes encoding arylalkylamine N-acetyltransferase (Aanat), a key enzyme in melatonin biosynthesis, and the melatonin receptor (Mel1c), along with the blood melatonin level. Chickens hatched in summer or winter were maintained under LD 16:8 and 8:16, corresponding to the respective photoperiods, as the seasonal control groups. Another set of chickens was kept in parallel under LL conditions and some were supplemented with melatonin to check the ability of exogenous hormone to antagonize the effects evoked by continuous light. Twelve-day-old chickens were sacrificed every 3 h over a 24-h period and the mRNAs of selected clock genes, Bmal1, Cry1, Per3, E4bp4, together with those of Aanat and Mel1c, were quantified in the isolated pineal glands. Our results indicate that the profiles of clock gene transcription are not dependent on the duration of the light phase, while LL conditions decrease the amplitude of diurnal changes, but do not abolish them entirely. Melatonin supplied in drinking water to the birds kept in LL seems to desynchronize transcription of the majority of clock genes in the summer, while in the winter, it restores the pattern, but not the diurnal rhythmicity. Rhythmic expression of Bmal1 appears to provide a direct link between the circadian clock and the melatonin output pathway, while the availability of cyclic melatonin is clearly involved in the canonical transcription pattern of Per3 in the chicken pineal gland. Regardless of the experimental conditions, a negative correlation was identified between the transcription of genes involved in melatonin biosynthesis (Aanat) and melatonin signal perception (Mel1c receptor).

Ultrastructural alterations of the endocrine glands in patients with Tay-Sachs disease have so far not been reported. Clinical observations of precocious puberty in baby girls with Tay-Sachs disease prompted an endocrine study which revealed an increase of either plasma luteinizing hormone or follicle stimulating hormone, or both, as well as an increase in 24-hour urinary estradiol, estriol, and testosterone levels. The ultrastructure of the pituitary, pineal, adrenal, and ovarian glands, and the cerebral cortex and hypothalamus from one of the children was studied in order to find a morphologic explanation for this phenomenon. In the anterior and posterior portions of the pituitary gland, cerebral cortex, and hypothalamus, typical Tay-Sachs lipid bodies were observed, whereas membranous lipid bodies were noted in the pineal gland. Adrenal and ovarian involvement were absent. The relationship of these organs to the precocious puberty, however, remains uncertain. The alteration in these endocrine glands is further evidence of the widespread distribution of these lipids, and suggests that the metabolic defect is ubiquitous in tissues of patients with Tay-Sachs disease.

The pineal gland is a small neuroendocrine organ involved primarily in the circadian rhythm by the secretion of melatonin [1]. In addition, the pain modulatory properties of melatonin are generally recognized but its involvement in neuropathic pain regulation is not fully understood. In fact, it is known that the activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization [2]. Moreover, melatonin showed an analgesic effect, in fact several works in animals [2] and in humans [3] underline its ability to inhibit hyperalgesia. In particular, intracerebroventricular and intraperitoneal melatonin, with its higher doses, produces a blockade of thermal hyperalgesia in mice with partial tight ligation of the sciatic nerve. The aim of our work is to characterize the morphological changes in peripheral structures, such as plantar skin and dorsal root ganglia (DRG) of rats in a neuropathic pain model (chronic constriction injury) after a single melatonin treatment monitoring the behaviour and the changes in NO-system using immunohistochemical techniques. The behavioural results show an increase of withdrawal latency during plantar test already after 30 min from melatonin administration. The immunohistochemical results suggest that melatonin plays a crucial role in keratinocytes-mediated neuropathic pain transmission through the modulation of nitroxidergic system, which could have also a protective role at this site. In addition, at DRG level the NO-system is maintained at low level. These results suggest that melatonin administration or modulation of pineal gland activity may have clinical utility in neuropathic pain therapy in the future.

In the mammalian pineal gland, the rhythm in melatonin biosynthesis depends on the norepinephrine (NE)-driven regulation of arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme of melatonin biosynthesis. A recent study showed that phytocannabinoids like tetrahydrocannabinol reduce AANAT activity and attenuate NE-induced melatonin biosynthesis in rat pineal glands, raising the possibility that an endocannabinoid system is present in the pineal gland. To test this hypothesis, we analyzed cannabinoid (CB) receptors and specific enzymes for endocannabinoid biosynthesis or catabolism in rat pineal glands and cultured pinealocytes. Immunohistochemical and immunoblot analyses revealed the presence of CB1 and CB2 receptor proteins, of N-acyl phosphatidyl ethanolamine hydrolyzing phospholipase D (NAPE-PLD), an enzyme catalyzing endocannabinoid biosynthesis and of fatty acid amide hydrolase (FAAH), an endocannabinoid catabolizing enzyme, in pinealocytes, and in pineal sympathetic nerve fibers identified by double immunofluorescence with an antibody against tyrosine hydroxylase. The immunosignals for the CB2 receptor, NAPE-PLD, and FAAH found in pinealocytes did not vary under a 12 hr light:12 hr dark cycle. The CB1 receptor immunoreaction in pinealocytes was significantly reduced at the end of the light phase [zeitgeber time (ZT) 12]. The immunosignal for NAPE-PLD found in pineal sympathetic nerve fibers was reduced in the middle of the dark phase (ZT 18). Stimulation of cultured pinealocytes with NE affected neither the subcellular distribution nor the intensity of the immunosignals for the investigated CB receptors and enzymes. In summary, the pineal gland comprises indispensable compounds of the endocannabinoid system indicating that endocannabinoids may be involved in the control of pineal physiology.

The discovery in 1953 of rapid eye movement (REM) sleep and the appreciation that sleep is a heterogeneous physiological state stimulated major research into sleep disorders. Electroencephalographic studies have shown that the amount of REM sleep changes with age. While newborns spend almost 50% of their sleep time in REM, the percentage of REM sleep decreases to 30% by the age of 3 months and to 20% by the age of 6 months. In addition, newborns enter REM sleep soon after the initiation of sleep, but by the age of 4 months entry into sleep assumes the adult pattern in which a significant period of non-REM sleep precedes the onset of REM sleep. Since reduction in the amount of REM sleep is associated with cerebral maturation and since the pineal gland has been implicated both in cerebral development and in the organization of REM sleep, the pineal gland may be involved in the maturation of the adult REM sleep pattern. Prior to the age of 3 months melatonin plasma levels are low and the characteristic circadian rhythms of melatonin are absent. Thereafter, melatonin secretion increases and circadian rhythmicity of melatonin becomes apparent. Thus, the abundance of REM sleep during the first 3 months of infancy is associated with deficient pineal melatonin functions, while the decline in the percentage of REM sleep coincides with the emergence of melatonin secretion coincident with the maturation of the pineal gland. I propose, therefore, that a state of low melatonin secretion is permissive for REM sleep and that maturation of the pineal gland retards REM sleep. This hypothesis is supported by the findings that melatonin suppresses REM sleep in cats and that in rats and humans pinealectomy induces a narcoleptic-like pattern of REM sleep which strikingly resembles that of the newborn and which is reversed by the administration of melatonin. A further hypothesis is advanced to explain the pathophysiology of narcolepsy in terms of a maturational defect of the pineal gland in infancy.

Central nervous system disease is globally common with dysfunction of the brain and spinal cord, which significantly affects the quality of life, such as sleep disturbances. Pineal gland is pivotal in regulating sleep cycles and circadian rhythms. And melatonin, secreted by pineal gland, promotes neurodevelopment and maintains neurohomeostasis, which is also pivotal in the modulation of central nervous system disorders. In recent years, studies have found that patients with central nervous system damage often have degeneration of the pineal gland, characterized by a decrease in pineal gland volume, reduced melatonin secretion, and even parenchymal calcification. An increasing number of Alzheimer's disease patients have been observed to exhibit pineal gland calcification. Research suggests that sleep disturbances accompanying central nervous system disorders can be attributed to the degeneration of pineal gland function, indicating a potential contribution of gland calcification to central nervous system diseases. Here, we review the recent research on pineal gland calculi and discuss the potential relationship between pineal gland calcification and various central nervous system diseases, contributing to a deeper understanding of the intricate mechanisms underlying neurological disorders.

The pineal organ is a derivative and integral component of the brain. In phylogeny it has changed from a 'third eye' capable of direct achromatic and/or chromatic responses to light to an endocrine gland influenced by visual stimuli from the retina. The outer segment of pineal photoreceptors contains a microspectrophotometrically detectable photopigment and an opsin-immunoreactive protein. Certain pinealocytes endowed with an outer segment display fluorophores of 5-HT/HTP and can be regarded as photoneuroendocrine cells. These photoneuroendocrine cells resemble cerebrospinal fluid-contacting neurons. The intrinsic circuitry (wiring diagram) of pineal photoreceptor organs has been only partly deciphered ; this holds true also for the neurotransmitters and synaptic patterns. Pineal photoreceptor organs are connected to the brain, i.e., to habenular, pretectal, thalamic, tegmental (reticular), and hypothalamic centers. The special anatomical and physiological features of the pineal organ enable it to translate photic information into neural and neuroendocrine responses.

BackgroundIt is now widely accepted that AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis. Recently, it has been shown to regulate circadian clocks. In seasonal breeding species such as sheep, the circadian clock controls the secretion of an endogenous rhythm of melatonin and, as a consequence, is probably involved in the generation of seasonal rhythms of reproduction. Considering this, we identified the presence of the subunits of AMPK in different hypothalamic nuclei involved in the pre- and post-pineal pathways that control seasonality of reproduction in the ewe and we investigated if the intracerebroventricular (i.c.v.) injection of two activators of AMPK, metformin and AICAR, affected the circadian rhythm of melatonin in ewes that were housed in constant darkness. In parallel the secretion of insulin was monitored as a peripheral metabolic marker. We also investigated the effects of i.c.v. AICAR on the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in brain structures along the photoneuroendocrine pathway to the pineal gland.ResultsAll the subunits of AMPK that we studied were identified in all brain areas that were dissected but with some differences in their level of expression among structures. Metformin and AICAR both reduced (p < 0.001 and p < 0.01 respectively) the amplitude of the circadian rhythm of melatonin secretion independently of insulin secretion. The i.c.v. injection of AICAR only tended (p = 0.1) to increase the levels of phosphorylated AMPK in the paraventricular nucleus but significantly increased the levels of phosphorylated ACC in the paraventricular nucleus (p < 0.001) and in the pineal gland (p < 0.05).ConclusionsTaken together, these results suggest a potential role for AMPK on the secretion of melatonin probably acting trough the paraventricular nucleus and/or directly in the pineal gland. We conclude that AMPK may act as a metabolic cue to modulate the rhythm of melatonin secretion.