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The protective effect of melatonin and epithalon on hypothalamic regulation of the reproductive function in female rats in a model of its premature aging and on the estrous cycles of aging animals in different lighting conditions
Abstract
Possible neuroprotective effects of melatonin (pineal gland hormone) and epithalon (peptide preparation) on estrous cycles and the central part of the reproductive function regulation in female rats under the influence of unfavorable ecological factors were studied. Estrous cycles of young, mature, and aging rats exposed to light pollution were characterized. The daily dynamics and average daily content of biogenic amines in the hypothalamic areas responsible for gonadoliberin synthesis and secretion were studied in animals of different age groups. The influence of the chemical effect on the noradrenergic system of the medial preoptic area and the dopaminergic system of median eminence with arcuate hypothalamic nuclei was studied in a model of premature aging of the reproductive function. It was established that the introduction of melatonin (pineal gland hormone) and epithalon (peptide preparation) is able to remove a number of the disturbances in the hypothalamic and ovarian parts of the reproductive system observed under conditions of permanent lighting and neurotoxic 1,2-dimethylhydrazine xenobiotic on the experimental animals. The results obtained indicate an important role of the pineal gland in the development of the circadian signal required for realization of the pre-ovulatory peak of gonadoliberin secretion and a protective effect of melatonin and epithalon, which is able to smooth away unfavorable ecological effects on the reproductive function of female rats with normal estrous cycles.
... This drug reinstated the normal daily dynamics of neurotransmitters in hypothalamic regions important for the production and release of gonadotropin-releasing hormone. It was suggested that Epitalon is particularly effective in mitigating adverse ecological impacts on the reproductive functions of young, adult, and aging female creatures when provided alongside another chemical derived from the pineal gland-Melatonin [98]. This activity of Epitalon could be connected with the ability of Epitalon to regulate the dopamine level in arcuate nuclei post-1,2-dimethylhydrazine injection [99]. ...
Epitalon, also known as Epithalon or Epithalone, is a tetrapeptide, Ala-Glu-Asp-Gly (AEDG), which was synthesized based on the amino acids composition of Epithalamin, a bovine pineal gland extract, prior to its discovery in pineal gland polypeptide complex solution. During the last 25 years, this compound has been extensively studied using in vitro, in vivo, and in silico methods. The results of these studies indicate significant geroprotective and neuroendocrine effects of Epitalone, resulting from its antioxidant, neuro-protective, and antimutagenic effects, originating from both specific and nonspecific mechanisms. Although it has been demonstrated that Epitalon exerts, among other effects, a direct influence on melatonin synthesis, alters the mRNA levels of interleukin-2, modulates the mitogenic activity of murine thymocytes, and enhances the activity of various enzymes, including AChE, BuChE, and telomerase, it remains uncertain whether these are the sole mechanisms of action of this compound. Moreover, despite the considerable volume of research on the biological and pharmacodynamic characteristics of Epitalon, the quantity of physico-chemical and structural investigations of this peptide remains quite limited. This review aims to conclude the most important findings from such studies, thus presenting the current state of knowledge on Epitalon.
Biological ageing is generally accompanied by a gradual loss of cellular functions and physiological integrity of organ systems, the consequential enhancement of vulnerability, senescence and finally death. Mechanisms which underlie ageing are primarily attributed to an array of diverse but related factors including free radical-induced damage, dysfunction of mitochondria, disruption of circadian rhythms, inflammaging, genomic instability, telomere attrition, loss of proteostasis, deregulated sensing of nutrients, epigenetic alterations, altered intercellular communication, and decreased capacity for tissue repair. Melatonin, a prime regulator of human chronobiological and endocrine physiology, is highly reputed as an antioxidant, immunomodulatory, antiproliferative, oncostatic, and endocrine-modulatory molecule. Interestingly, several recent reports supprot melatonin as an anti-ageing agent whose multifaceted functions may lessen the consequences of ageing. This review depicts four categories of melatonin's protective effects on ageing-induced molecular and structural alterations. We also summarize recent findings related to the function of melatonin during ageing in various tissues and organs.
This review describes the role of biogenic amines in the hypothalamic regulation of ovarian cycles in female rats. The mechanisms of action of industrial xenobiotics and experimental hyperhomocysteinemia, which induces premature aging of the reproductive function, are discussed. The point of view that the damaging action of reactive oxygen species is the basis of the unified response of hypothalamic regulation of reproductive cycles to external and internal neurotoxic impacts is substantiated. We describe the involvement of melatonin and short regulatory peptides in antioxidant protection of the reproductive system during aging.
В настоящее время интенсивно изучаются механизмы регуляции репродукции, обусловливающие передачу сигнала от супрахиазматических ядер к преоптической области и срединному возвышению гипоталамуса, в которых осуществляется синтез и секреция гонадолиберина. Как установлено в экспериментах на самках крыс, важная роль в этих процессах принадлежит биогенным аминам и опиоидам гипоталамуса, которые имеют характерные суточные ритмы, исчезающие при старении и утрате репродуктивной функции. Проведенными нами экспериментами обнаружено, что в преоптической области, срединном возвышении и супрахиазматических ядрах гипоталамуса половозрелых самок крыс наблюдается суточная динамика биогенных аминов, нарушающаяся под влиянием нейротоксических соединений — толуола и 1, 2-диметилгидразина. Попытка использовать для синхронизации нарушенных биоритмов экзогенный мелатонин оказалась безуспешной, поскольку он сам по себе вызывал нарушения суточной динамики исследуемых показателей. На основе проведенных исследований и анализа литературных данных выдвигается гипотеза о роли имеющих противоположную направленность суточных ритмов этих нейромедиаторов в формировании проэстрального пика секреции гонадолиберина. Нарушение суточных ритмов исследуемых показателей под влиянием экзогенного мелатонина объясняется с позиций проявления побочных эффектов эпифизарного гормона при превышении его физиологического уровня.
Our data on elucidation of the role of catecolaminergic systems of the hypothalamusin gonadotropin-releasing hormone (GnRH) pre-ovulatory surge formation in female ratsis presented in this study. It has been shown that diurnal variations of norepinephrine(NE) in the medial pre-optic area (MPA) and of dopamine (DA) in the median eminencewith arcuate nuclei (ME-Arc) do not depend on estrous cycle stage, which proves theirsubordinacy to the central pace-maker of circadian rhythms in the suprachiasmatic nuclei(SCN) of the hypothalamus. Moreover, both noradrenergic and dopaminergicmechanisms of GnRH synthesis and secretion regulation are controlled by a hormonalsignal originating from the ovaries, and by a circadian signal originating from the SCN.NE, rather than DA, has a truly circadian rhythm in the MPA. Our data about the effect ofa single subcutaneous injection of 1,2-dimethylhydrazine (DMH) (21 mg/kg b.w.), aswell as of 2-month inhalation of toluene (50 and 500 mg/m3), on the contents of NE andDA in the hypothalamic structures and on the circadian/diurnal rhythms of the studiedneurotransmitters is presented. The neurotoxicants were shown to change all of therhythms observed in the control. Also, we studied the protective effect of melatonin andsome pineal gland peptides on the daily dynamics of the biogenic amines in the samebrain areas affected by DMH. We have found that the administration of melatonin couldeliminate some disturbances of the hypothalamic link of the reproductive system byrestoring the circadian rhythm of NE in the MPA. A polypeptide preparation from thepineal gland epithalamin induced the recovery of the daily dynamics of theneurotransmitter in the mentioned hypothalamic structure. A synthetic peptide epitalon(Ala-Glu-Asp-Gly), which maintains a physilogical level of melatonin, was moreeffective in the ME-Arc. The data obtained confirm the idea that the studiedneurotoxicants affect not only circadian (NE), but also diurnal (DA) rhythms. It issuggested that the effect of the neurotoxicants on the content and diurnal rhythms of theneurotransmitters in the studied hypothalamic structures is due to its affecting activitiesof the enzymes of the biogenic amines synthesis, synaptic transmission, melatoninsynthesis and secretion rhythms. Our results indicate that the pineal gland plays animportant role in the modulation of the circadian signal necessary for GnRH surge duringthe proestrus stage.
The possible role of melatonin in the regulation of the reproductive system of female rats during ageing was investigated in middle-aged female rats showing irregular duration of the oestrous cycle (n = 30). Blood samples were obtained by jugular venepuncture during the oestrous cycle in control rats. After this experiment was completed, the female rats were treated with melatonin for 2 months and blood samples were obtained at different stages of the oestrous cycle. Plasma LH, FSH and prolactin concentrations were significantly increased in the afternoon of the day of pro-oestrus after melatonin treatment compared with control rats. Moreover, FSH concentrations too were significantly increased on the morning of pro-oestrus and oestrus in melatonin treated rats compared with control rats. Similarly, oestradiol concentrations were significantly higher on the morning of pro-oestrus in melatonin treated rats compared with controls. Another group of rats showing irregular duration of the oestrous cycle was used to study the possible effect of melatonin treatment on the timing of pro-oestrous surges of LH and FSH. The results showed that LH and FSH peak values occurred at 5 h after melatonin treatment. Pituitary responsiveness to LHRH in a 90 min test was also studied in middle-aged rats showing irregular duration of the oestrous cycle that had been injected for 1 month with either melatonin or saline. Prolactin response was unaffected by exogenous melatonin, but a stimulatory effect of melatonin on LH and FSH pituitary responsiveness to LHRH was observed. The results indicate an improved function of the neuroendocrine-reproductive axis in middle-aged rats after melatonin treatment.
Our data on the contents of norepinephrine (NE), dopamine (DA) and the metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) measured in the suprachiasmatic nuclei (SCN), preoptic area (PA) and median eminence (ME) of hypothalamus of rats after single subcutaneous injection of 1,2-dimethylhydrazine (DMH) as well as the effect of this carcinogen on formation of reactive oxygen species (ROS) in the PA are presented in this paper.
Diurnal changes of DA in all studied brain structures and of NE in the PA have been observed in the control group. Their morning levels were higher than evening ones. Rhythms of 5-HIAA in the SCN and diurnal changes of ROS formation have been shown to have contrary changes in control. Both the morning (11 a.m.) and evening (11 p.m.) subcutaneous administration of DMH at the dose of 21 mg/kg of body weight resulted in changes of all rhythms observed in control. In some cases a phase shift was found, in others the rhythms of neurotransmitters and ROS formation disappeared entirely.
The data obtained confirm the idea of dopaminergic and serotoninergic systems taking part in mechanisms of a response of the hypothalamic nuclei to non-photic stimuli. It is suggested that the effect of DMH on the content and diurnal rhythms of neurotransmitters in the hypothalamic structures under study is due to its affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms. The change in ROS formation that is caused by administration of DMH is likely to be due to a disturbance of diurnal rhythms of neurotransmitters that are one of the sources of formation of free radicals in the brain.
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women. Recently, it has become clear that estrogens act on more than just the hypothalamus, pituitary, ovary, and other reproductive organs. In fact, they play roles in a wide variety of nonreproductive functions. With the increasing life span of humans from approximately 50 to 80 years and the relatively fixed age of the menopause, a larger number of women will spend over one third of their lives in the postmenopausal state. It is not surprising that interest has increased in factors that govern the timing of the menopause and the repercussions of the lack of estrogen on multiple aspects of women's health. We have used animal models to better understand the complex interactions between the ovary and the brain that lead to the menopause and the repercussions of the hypoestrogenic state. Our results show that when rats reach middle age, the patterns and synchrony of multiple neurochemical events that are critical to the preovulatory gonadotropin-releasing hormone (GnRH) surge undergo subtle changes. The precision of rhythmic pattern of neurotransmitter dynamics depends on the presence of estradiol. Responsiveness to this hormone decreases in middle-aged rats. The lack of precision in the coordination in the output of neural signals leads to a delay and attenuation of the luteinizing hormone surge, which lead to irregular estrous cyclicity and, ultimately, to the cessation of reproductive cycles. We also have examined the impact of the lack of estrogen on the vulnerability of the brain to injury. Our work establishes that the absence of estradiol increases the extent of cell death after stroke-like injury and that treatment with low physiological levels of estradiol are profoundly neuroprotective. We have begun to explore the cellular and molecular mechanisms that underlie this novel nonreproductive action of estrogens. In summary, our studies show that age-related changes in the ability of estradiol to coordinate the neuroendocrine events that lead to regular preovulatory GnRH surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.
In mammals, the exact role of melatonin (Mel) in the circadian timing system remains to be determined. However, exogenously administered Mel, as reported in the present mini-review, has been shown to affect the circadian clock. The sites and mechanisms of action involved in this "chronobiotic" effect of Mel have begun to be characterized. The suprachiasmatic nuclei (SCN) appear to be an important site for the entrainment effect of Mel and the presence of Mel receptors appears to be a prerequisite. However, the pharmacological dose of Mel needed to entrain circadian rhythms means that very probably other sites and mechanisms also play a role.
Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.
The neurohormone melatonin is released from the pineal gland in close association with the light-dark cycle. There is a temporal relationship between the nocturnal rise in melatonin secretion and the 'opening of the sleep gate' at night. This association, as well as the sleep promoting effect of exogenous melatonin, implicates the pineal product in the physiological regulation of sleep. Aging is associated with a significant reduction in sleep continuity and quality. A decreased production of melatonin with age is documented in a majority of studies. Diminished nocturnal melatonin secretion with severe disturbances in sleep/wake rhythm has been consistently reported in Alzheimer's disease (AD). A recent survey on the effects of melatonin in sleep disturbances, including all age groups, failed to document significant and clinically meaningful effects of exogenous melatonin on sleep quality, efficiency and latency. However, in clinical trials involving elderly insomniacs and AD patients suffering from sleep disturbances exogenous melatonin has repeatedly been found to be effective in improving sleep. The results indicate that exogenous melatonin is more effective to promote sleep in the presence of a diminished production of endogenous melatonin. A MT1/MT2 receptor analog of melatonin (ramelteon) has recently been introduced as a new type of hypnotics with no evidence of abuse or dependence.
In mammals, the suprachiasmatic nuclei (SCN) regulate the timing of LH surges. Recent evidence suggests that vasoactive intestinal peptide (VIP), an abundantly expressed neuropeptide of the SCN, communicates time of day information from the SCN to GnRH neurons. VIP levels in the SCN decrease with age and may be responsible for alterations in LH surges that become apparent in middle-aged rats. We wished to determine whether suppression of VIP synthesis, through antisense oligonucleotides (oligos) directed at the SCN, results in 1) selective suppression of VIP levels in the SCN and 2) aging-like changes in the secretion of LH and PRL. To test the specificity of antisense oligo treatment, rats were ovariectomized and treated with estradiol. Antisense or control random oligos were infused into the peri-SCN region through stereotaxically placed bilateral cannulas. Beginning at lights off, rats were maintained in constant dim red illumination throughout the remainder of the experiment. They were killed at speci...
This chapter summarizes the current knowledge about the anatomical and physiological interaction among the three components of the neural circuitry—that is, the possible anatomical pathways and putative neurotransmitters involved. Whether a rat exhibits a female- or male-like pattern of luteinizing hormone (LH) secretion in adulthood appears to depend on steroidal conditioning during a critical period of development. The actual increase in progesterone at the time of the surge in an individual female rat strongly determines both the timing and height of the proestrous luteinizing hormone (LH) surge that are in turn tightly associated with the degree and duration of sexual receptivity of the animal. The neuronal system responsible for preovulatory secretion of LH in the female, thus, includes at least three major components—(1) the gonadotropin-releasing hormone (GnRH) neurons, (2) hormone sensitive neurons in the medial preoptic area (MPO) that transmit the stimulatory effects of estrogen and progesterone to the GnRH neurons, (3) a circadian timing device—the suprachiasmatic nucleus (SCN)—that entrains the activity of the GnRH system, and subsequently the LH surge to the appropriate moment of the light dark-cycle.
The luteinizing hormone surge in the female rat is not only induced by the positive feedback of estradiol, but also by circadian signals originating in the suprachiasmatic nucleus (SCN). In a previous study we showed that administration of vasopressin, an SCN transmitter present in preoptic projections, induced an LH surge in animals bearing complete lesions of the SCN. This strongly suggests vasopressin as a stimulatory circadian signal for the timing of the LH surge. In the present study we investigated during which time window vasopressin may act in the medial preoptic area to stimulate LH secretion in SCN-intact female rats. Vasopressin or a specific V1a receptor antagonist was administered into the MPO by a reverse microdialysis technique during different time windows, and plasma LH concentrations were measured. Vasopressin stimulated the LH surge in 30% of the animals, when administered during the second half of the light period, but during the first half of the light period no effects were observed. Administration of the V1a receptor antagonist, however, did not affect the LH surge. These data confirm our previous results that vasopressin is a stimulatory factor for the LH surge also in SCN-intact animals, and indicate that a certain time window is available for such stimulation. We hypothesize that vasopressin in the SCN-intact animal may act as a circadian signal during a specific time window to induce the LH surge. The time window is the result of other SCN regulatory systems that are involved in the preparation of the LH surge.
Major environmental variables such as daily and seasonal changes of light and temperature regulate the daily circadian variations of synthesis and release of the pineal neurohormone N-acetyl-5-methoxytryptamine (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent, and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured by antibody production, by thymus weight, and by the capacity of stressed- and evening-melatonin-treated mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology and generation of immunocompetence and tolerance during ontogeny.
The purpose of the following study was to assess the changes in the proestrous hormone profile in middle-aged cycling rats to better understand the inter-relationship and possible interaction of these hormones during the transition to estrous acyclicity. Median eminence LHRH concentrations and serum LH, FSH, estradiol and progesterone concentrations were measured in young (3-4 months old) and middle-aged (8-10 months old) proestrous rats at 0900, 1200, 1500 and 1800h. The data demonstrate that (1) baseline hormone concentrations prior to the surge at 0900h are the same in middle-aged and young rats; (2) the proestrous gonadotropin surge is temporally delayed in middle-aged rats; (3) this delay is preceded by lower median eminence LHRH concentrations and serum estradiol concentrations at 1200h; (4) serum progesterone concentrations are lower in middle-aged rats during the preovulatory gonadotropin surge (at 1500 and 1800h) probably as a consequence of the delayed LH surge.
The roles of hypothalamic norepinephrine (NE) and dopamine (DA) in the regulation of LH and PRL are controversial. In the present studies, we used HPLC and push-pull perfusion to measure NE and DA releases in the medial preoptic area (MPA) of conscious, freely moving rats. Serum LH and PRL were determined in separate groups of rats with indwelling venous cannulas. In young (4- to 5-month-old) rats, concomitant with proestrous surges of serum LH and PRL, NE release in the MPA increased gradually to reach a peak at 1800 h, whereas DA release decreased gradually to its lowest level at 2000 h. Compared to the young animals, in middle-aged (8- to 10-month-old) animals, the proestrous surge of PRL was unaltered, but the LH surge was delayed and attenuated. The pattern of DA release in the middle-aged animals was also unaltered, but the peak in NE release was markedly attenuated, although the average NE release was increased compared to that in the young proestrous animals. In young diestrous rats and old (22- to 24-month-old), persistently diestrous rats, in which serum LH and PRL are known to be stable, both NE and DA releases were devoid of fluctuations. However, in the young diestrous animals, the average NE and DA releases were significantly increased compared to those in the young proestrous animals, whereas in the old, persistently diestrous animals, NE and DA releases were markedly reduced compared to those in the young diestrous animals. These data lead us to conclude that NE, through its stimulatory action, may be the primary regulator of LH release, and that it is the pattern, rather than the level, of NE release that appears to be critical in determining the pattern of LH release. DA, through its inhibitory action, appears to control PRL only and probably has no association with LH release. By tracing NE and DA activities from adulthood through middle-age to senescence, these studies revealed that the marked reductions in catecholamines in old age are preceded by a transitory increase in NE activity in middle-age, and that the cyclic increase in NE activity associated with the LH surge begins to diminish in middle age and disappears completely in old age.
Effects of pinealectomy and melatonin replacement on the timing of the preovulatory luteinizing hormone (LH) surge were examined in female rats housed under a light-dark cycle (lights on 06:30-18:30 h). Animals were pinealectomized or sham-operated 21-28 days before bleeding. They were sequentially bled in the afternoon of proestrus through the indwelling cardiac cannula without anesthesia. Proestrous LH surges were observed in all pinealectomized rats, but the onset times of the LH surge in these animals showed a significantly greater variance than those in sham-operated controls. A single melatonin injection at 18:00 or 21:00, shortly before or after the light-dark transition, on the day before proestrus (diestrus II) reduced the variance in the LH surge onset in pinealectomized rats in a dose-dependent manner. In contrast, melatonin injected at 14:00 or 23:00 on diestrus II or at 04:00 on proestrus was ineffective. These results showed that the pineal gland is involved in controlling the timing of the proestrous LH surge in the rat. The pineal signal may be transmitted by melatonin, a major product of the gland.
The mechanism(s) by which melatonin (MEL) can regulate gonadotropin secretion remains unresolved. Accordingly, we used acute in vitro incubations of male rat hypothalamic tissues to investigate effects of MEL on hypothalamic gonadotropin-releasing hormone (GnRH) secretion. At 10:00 h (3.5 after lights on), addition of 1 nM MEL to the medium inhibited (p = 0.028) GnRH release from the median eminence (ME) by 24%, 100 nM MEL had no significant effect on GnRH release, and 10 microM MEL tended to inhibit (p = 0.056, 21%) GnRH release. At 15:00 h, none of these MEL dosages significantly altered GnRH release from the ME. When the effect of a lower range of MEL dosages was evaluated, 1 nM MEL again inhibited (24%, p = 0.032) GnRH release from the ME at 10:00 h, and a linear dose-response relationship between initially increasing dosages (0, 0.01, 0.1, 1 nM) of MEL treatment and decreasing GnRH release was evident (r = 0.88), although a further 10 fold increase in MEL dosage (10 nM) resulted in a loss of suppression by MEL. Treatment with these dosages of MEL did not significantly alter ME GnRH release at 15:00 h. In contrast to the results with the ME alone, treatment with 0.1 microM MEL increased (p = 0.018) GnRH release from the arcuate-median eminence region (ARC-ME) by 60.2% at 10:00 h, whereas treatment with either 0.001 or 10 microM MEL did not significantly affect GnRH release. Treatment with these dosages of MEL did not significantly alter ARC-ME GnRH release at 15:00 h.(ABSTRACT TRUNCATED AT 250 WORDS)
In mammals, the suprachiasmatic nuclei (SCN) regulate the timing of LH surges. Recent evidence suggests that vasoactive intestinal peptide (VIP), an abundantly expressed neuropeptide of the SCN, communicates time of day information from the SCN to GnRH neurons. VIP levels in the SCN decrease with age and may be responsible for alterations in LH surges that become apparent in middle-aged rats. We wished to determine whether suppression of VIP synthesis, through antisense oligonucleotides (oligos) directed at the SCN, results in 1) selective suppression of VIP levels in the SCN and 2) aging-like changes in the secretion of LH and PRL. To test the specificity of antisense oligo treatment, rats were ovariectomized and treated with estradiol. Antisense or control random oligos were infused into the peri-SCN region through stereotaxically placed bilateral cannulas. Beginning at lights off, rats were maintained in constant dim red illumination throughout the remainder of the experiment. They were killed at specific times, brains were microdissected, and VIP concentrations in the SCN, paraventricular nuclei, and cortex were assayed. As a control for the specificity of antisense VIP treatment, we monitored the levels of arginine vasopressin in the SCN. To test the effects of antisense treatment on the pattern of plasma LH and PRL secretion, blood samples were collected from atrial catheters from 1200-2000 h, and plasma samples were assayed for LH and PRL. The results indicate that the effects of antisense treatment were discrete, as they suppressed VIP concentrations in the SCN, but had no effect on VIP concentrations in the paraventricular nuclei or cortex or on arginine vasopressin concentrations in the SCN. Peak LH levels during the surge were delayed and attenuated in antisense-treated animals compared to random oligo-treated control rats in a manner strikingly similar to that observed previously in middle-aged rats. Likewise, PRL, which was unaffected in middle-aged rats, was also unaffected by targeted suppression of VIP. In summary, our findings clearly demonstrate that antisense VIP oligos suppress VIP levels in the SCN and do not affect peptide concentrations in other regions of the brain or other neuropeptides in the SCN. Further, we show that suppression of a single neuropeptide in the SCN can mimic the effects of age on the estradiol-induced surges of LH and PRL. These data support a central role for suprachiasmatic VIP in the regulation of the LH surge and suggest that age-related perturbations in the integrity of this axis may account for alterations in the pattern of LH secretion observed during middle age.
The luteinizing hormone surge in the female rat is the result of the integration of multiple signals within the medial preoptic area. The medial preoptic area contains gonadotropin-releasing hormone neurons that are responsible for the release of luteinizing hormone, neurons containing estrogen receptors and terminals originating from the suprachiasmatic nucleus with, for example, vasopressin as neurotransmitter. Both the medial preoptic area and suprachiasmatic nucleus are crucial for the occurrence of luteinizing hormone surges, since lesioning of either nucleus prevents pre-ovulatory and steroid-induced luteinizing hormone surges. In this study, we investigated whether vasopressin in the medial preoptic area could be the daily neuronal signal from the suprachiasmatic nucleus responsible for the timing of the luteinizing hormone surge. Vasopressin (50 ng/microl) or Ringer solution was administered by reverse microdialysis from Zeitgeber times 7.5 to 12.5 into the medial preoptic area of ovariectomized, estradiol-treated rats. The suprachiasmatic nucleus was lesioned to remove all cyclic luteinizing hormone secretion. This was evaluated by monitoring behavioral activity; animals that were arrhythmic were included in the experiments. Hourly blood samples were taken to measure plasma luteinizing hormone levels. Preoptic vasopressin administration induced a surge-like luteinizing hormone pattern in suprachiasmatic nucleus-lesioned animals, whereas constant, basal luteinizing hormone levels were found in the control animals. These data show that vasopressin, by itself, is able to trigger the luteinizing hormone surge in suprachiasmatic nucleus-lesioned rats. We propose that vasopressin is a timing signal from the suprachiasmatic nucleus responsible for the activation of the hypothalamo-pituitary-gonadal axis in the female rat.
Levels of norepinephrine (NE), dopamine (DA) and the main metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the suprachiasmatic nuclei (SCN), preoptic area (PA), and median eminence (ME) of hypothalamus of rats after sole subcutaneous injection of 1,2-dimethylhydrazine (SDMH). Circadian changes of DA in all the brain structures under study as well as of NE in PA were observed in the control group, their levels in the mornings being higher than in the evenings; a circadian change of 5-HIAA in SCN had an opposite tendency. Both the evening (11 p.m.) and morning (11 a.m.) administrations of SDMH at the dose of 21 mg/kg body weight resulted in disturbances of all the circadian rhythms observed in control. In some cases only a 12 hrs circadian rhythms phase shift was found, in the others these rhythms of neurotransmitters disappeared entirely. The evening administration of SDMH, unlike the morning one, resulted in an increase in total NE content in the hypothalamic structures under study. It is suggested that the effect of SDMH on the levels and circadian rhythms of neurotransmitters in the hypothalamic structures under study is due to affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms, as well as to its genotoxic influence upon the genes controlling circadian actions.
Influence of peptide bioregulators and melatonin on parameters of biological age and longevity of mice
- V N Anisimov
- V Khavinson
- Kh
- N Zavarzina
- Yu
- VN Anisimov
Role of epiphysis (pineal glad) in aging)
- V N Anisimov
- VN Anisimov
Reproductive health as the criteria of bioecological assessment of environment
- E K Ailamazyan
- T V Belyaeva
- E G Vinogradova
- I A Shutova
- EK Ailamazyan
Study of toxic effect of prenatal hyperhomocysteine anemia on a progeny
- A V Arutjunyan
- L S Kozina
- V A Arutyunov
- AV Arutjunyan
Influence of melatonin on hypothalamic regulation of reproductive functions in rats at the constant effect of xenobiotics, Neirokhimiya
- G O Kerkeshko
- M G Stepanov
- A V Korenevskii
Pineal’naya zheleza i vozrastnaya patologiya (mekhanizmy i korrektsiya) (Pineal Gland and Age Pathology: Mechanisms and Correction)
- N D Goncharova
- V Khavinson
- Kh
- B A Lapin
- ND Goncharova
Relationship between circadian and ovarian cycles in hypothalamic regulation of reproduction
- A V Korenevskii
- Yu P Milyutina
- M G Stepanov
- AV Korenevskii
Peptidy epifiza i timusa v regulyatsii stareniya (Importance of Peptides of Epiphysis and Thymus in Aging Regulation)
- V Khavinson
- Kh
- V G Morozov
- VKh Khavinson
Biologicheskii vozrast i starenie: vozmozhnosti opredeleniya i metody korrektsii (The Methods of Determination and Correction of
- A A Kishkun
- AA Kishkun
Disruption of circadian rhythms of biogenic amines in hypothalamus of the rats after introduction of 1,2-dimethylhydrasine
- A V Arutjunyan
- G O Kerkeshko
- V N Anisimov
- AV Arutjunyan
Investigation of mechanism of disruption of hypothalamic regulation of reproductive functions
- A V Arutjunyan
- G O Kerkeshko
- M G Stepanov
- AV Arutjunyan
Peptidnye bioregulyatory (25-letnii opyt eksperimental’nogo i klinicheskogo izucheniya) (Peptide Bioregulators: 25 Years of Experimental and Clinical Studies)
- V G Morozov
- V Khavinson
- Kh
- VG Morozov
Molekulyarnye i fiziologicheskie mekhanizmy stareniya (Molecular and Physiological Mechanisms of Aging)
- V N Anisimov
- VN Anisimov
Peptidnye bioregulyatory i starenie (Peptide Bioregulators and Aging)
- V Khavinson
- Kh
- V N Anisimov
- VKh Khavinson
Influence of melatonin on hypothalamic regulation of reproductive functions in rats at the constant effect of xenobiotics
- G O Kerkeshko
- M G Stepanov
- A V Korenevskii
- GO Kerkeshko
Disturbances of diurnal rhythms of biogenic amines contents in hypothalamic nuclei as an evidence of neurotropic effects of enterotropic carcinogen 1,2-dimethylhydrazine
- A V Arutjunyan
- G O Kerkeshko
- V N Anisimov
- AV Arutjunyan
Circadian and diurnal rhythms of catecholamines in hypothalamic areas responsible for regulation of reproduction in female rats are disturbed by neurotoxicants and corrected by melatonin
- A V Korenevsky
- Yu P Milyutina
- M G Stepanov
- AV Korenevsky
Disruption of neuromedial link of hypothalamic regulation of reproductive function affected by neurotoxic xenobiotics
- A V Arutjunyan
- M G Stepanov
- A V Korenevskii
- AV Arutjunyan