Dysfunction of central dopaminergic systems has been implicated in neuroendocrine, neurodegenerative and psychiatric disorders. Monoamine oxidase and catechol-Omethyltransferase represent the key catabolic enzymes of dopamine, terminating neurotransmission following synaptic release of this catecholamine. Thus, both enzymes have been associated with the pathology of dopaminergic systems and represent therapeutic targets elf enormous clinical importance. Some neuroendocrine and circadian effects of melatonin have been attributed to an antidopamimetic effect of this pineal hormone in the hypothalamus and pituitary. Furthermore, both melatonin and dopamine modulate the behavioural output of the mesencephalic dopaminergic pathways of the basal ganglia, including movement disorders. However, the biochemical basis for the tonic inhibitory effect of melatonin in the nigro-striatal pathway has been poorly delineated. Thus, this study determined whether melatonin influences dopaminergic function in the corpus striatum of the Wistar rat by modulating monoamine oxidase and catecholO- methyltransferase activity. Reciprocally, the putative existence of an intrapineal dopaminergic system was investigated by determining the effect of selective dopaminergic agents, R-( -)apomorphine, haloperidol and dopamine, on indole metabolism of the pineal gland. The akinetic state of drug-induced catalepsy was employed as an animal model of Parkinson's disease to probe the neurotransmitter systems involved in the behavioural effects of melatonin. Indole metabolism was a reliable indicator of state-dependent metabolic fluxes in pineal gland function. These included a robust diurnal and seasonal variation in N-acetylserotonin and melatonin biosynthesis, and photoperiod- and drug-induced alterations of Inftabolism. The predominant changes could be attributed to an effect on serotonin N-acetyltransferase activity and/or the melatoninl5-methoxytryptophol ratio. Pineal 5-methoxyindole biosynthesis was determined primarily by the bioavailability of the corresponding 5-hydroxyindole and its affinity for hydroxyindole-O-methyltransferase. Evidence was found for the negative feedback or paracrine control of pineal indole metabolism by melatonin. A high inter-individual variability was observed in the biosynthesis of N-acetylserotonin and melatonin biosynthesis, and the weight of the pineal glands. Accordingly, the rats could be classified as either high or low capacity producers of these two indoles. R-(-)-apomorphine and dopamine in vitro, but not acute haloperidol in vivo, had dose- and phase-dependent effects on pineal indole metabolism. The predominant effect was a suppression of the scotophase-dependent induction ofN-acetylserotonin and melatonin biosynthesis by dopamine and R-( -)-apomorphine. It is postulated that these agonists inhibited nocturnal N-acetyltransferase activity via postsynaptic pineal D2 or D2-like receptors. The observed modulatory nature of the intrapineal dopaminergic system suggests that dopamine may be involved in the long-term regulation of pineal indole biosynthesis. Several lines of evidence are presented that the activity of striatal monoamine oxidase A and catechol-O-methyltransferase, represented predominantly by the soluble isoform, is statedependent and regulated in vivo by endogenous melatonin. Firstly, both enzymes showed a daynight variation in activity. Secondly, acute and subchronic administration and photoperiod manipulation studies indicated that both exogenous and endogenous melatonin inhibited each enzyme in a chronotypic fashion, with a more robust effect against catechol- -methyltransferase. The intensity of the in vivo effects was critically dependent on the dose, duration, route and the phase-timing of administration during the light dark cycle, and the length of the exposure to constant light. Melatonin in vitro had no effect on basal or Mg2+ -induced catechol-Omethyltransferase activity. Thus, it is proposed that the in vivo effects of the hormone can be attributed to a time-dependent change in the amount of active molecules of this enzyme. In contrast, melatonin and numerous other endogenous indolic compounds were found to be reversible inhibitors of striatal monoamine oxidase A in vitro. Structure-activity modeling revealed that the 5-methoxy moiety on the indole nucleus and substitution of the free primary amine of these compounds were the principal determinants of the potency and time-dependency of inhibition. Thus melatonin most likely has a direct inhibitory effect in vivo at the level of the active site of monoamine oxidase A. Exogenous melatonin alone had no cataleptogenic potential whereas a variety of behavioural responses were observed following intraperitoneal administration of y-hydroxybutyrate. The latter responses were state-dependent with day-night variations in intensity. Furthermore, yhydroxybutyrate stimulated melatonin biosynthesis during the photophase both in vitro and in vivo. These results point to a possible involvement of melatonin in the behavioural and neurochemical effects of y-hydroxybutyrate. Thus the general conclusion is that dopamine and melatonin display functional antagonism at the level of the pineal gland and corpus striatum of the Wistar rats. Therefore melatonin may be an important homeostatic modulator of dopaminergic neurotransmission throu~out the central nervous system. Furthermore, the putative existence of a functional pineal-striatal axis would greatly strengthen the argument for a holistic concept of brain homeostasis. The ability of endogenous melatonin to regulate monoamine oxidase A and catechol-O-methyltransferase may represent an alternative strategy for the treatment of disorders associated with these enzymes.

As soon as the building of the body is completed, the ageing process begins. In the natural course of events, the functioning of some organ systems finally ebbs below the threshold necessary to maintain the body, resulting in death. This occurrence is relatively rare, because diseases superimpose themselves upon the ageing process, bringing premature death resulting from pathological causes. This study focused on the cholinergic system of the rat forebrain. The cholinergic neurons in the brain are said to be involved in memory and learning, and a decrease in the activity of its enzymes has been reported in certain diseases, such as Alzheimer's disease. In the present study, the in vitro effects on the cholinergic system, of aluminium and mercury and tryptophan metabolites, kynurenic acid and quinolinic acid, are determined. Aluminium has been considered as a possible factor in Alzheimer's disease. Mercury in high concentrations is toxic, and its use in amalgam for dental treatment is under consideration with regard to its possible role in promoting neurological disease. The tryptophan metabolites increase in the brain with age and may have a role in pathological diseases. Quinolinic acid, when administered in toxic concentrations produces a possible model for Huntington's disease. This study investigated the effects of the above mentioned toxins on: (1) The synthesis of acetylcholine by choline acetyltransferase; (2) The specific binding of acetylcholine muscarinic receptors; (3) The degradation of acetylcholine by acetyl cholinesterase, Choline acetyltransferase activity did not change in the presence of aluminium chloride, kynurenic acid and quinolinic acid from 1 nM to 1 mM. Mercuric chloride had no significant effect on the enzymes activity from a concentration of 1 nM- 1 pM. At 10 pM there was a significant decrease in cholineacetyltransferase activity (P < 0.001). Enzyme activity continued to decrease at 100 pM (P < 0.0002). At 1 mM, enzyme activity was virtually non existent (P < 0.0001). Acetyl cholinesterase activity was not affected by aluminium chloride, kynurenic acid and quinolinic acid. Mercuric chloride from 1 pM - 1 mM significantly reduced the enzyme activity (P < 0.05). The binding of the antagonist, [³H] quinuclidinyl benzilate (QNB), to acetylcholine muscarinic receptors, revealed that aluminium chloride did not affect the binding of the antagonist, in the concentration range of 1 nM - 100 pM, to the receptors. At 1 mM, aluminium chloride appears to increase the sensitivity of the receptors for the ligand (P < 0.01). Mercuric chloride also does not appear to have any significant effect on receptor binding in this range. However, at 1 mM there appears to be a very significant decrease in receptor binding (P < 0.01). This decrease may be attributed to the interaction of mercury with the sulfhydryl groups in muscarinic receptors. Kynurenic acid had no effect on the receptor binding. Quinolinic acid, in the concentration range from 10 nM - 1 mM increased the binding ofthe receptor to [3Hi QNB significantly (P < 0.001). The study also investigated the effect of the tryptophan metabolites of the kynurenine pathway on pineal indole metabolism. The kynurenine pathway is a major route of tryptophan metabolism in the pineal gland, along with indole metabolism. Investigations showed that kynurenic acid produced a decrease in N-acetylserotonin concentrations ( P < 0.001) and melatonin concentrations (P < 0.003). Further experiments using quinolinic acid produced a similar decrease in N-acetylserotonin (P < 0.001) and melatonin (P < 0.015). A decrease was also noted in the level of 5-methoxytryptophol (P < 0.0005). These findings suggest that aluminium chloride, kynurenic acid and quinolinic acid have no possible role in the decrease of activity of cholinergic enzymes which is observered in diseases such as Alzheimer's disease. The results regarding the effect of mercury chloride on the cholinergic system suggest that low exposure to the toxin will not adversely effect the enzymes. The decrease in N-acetylserotonin and melatonin concentrations reported here, may be a result of kynurenic acid and quinolinic acid having an inhibitory effect on the enzyme, serotonin Nacetyltransferase, which is responsible for the conversion of serotonin to N-acety/serotonin.

The purpose of this thesis is to critique the literature focusing on the role of pineal gland volume and function and the development of schizophrenia by asking the question, "What is the relationship between pineal gland physiologic function and development and symptom severity of schizophrenia? It is crucial that health care providers continue advocate for better understanding of schizophrenia in order to develop a more appropriate treatment and relive the suffering of those with schizophrenia. A review of published literature focusing on the pineal glands association with schizophrenia was performed using several databases including: ScienceDirect, PubMED, Google Scholar, Cumulated Index to Nursing and Allied Health Literature (CINAHL), and Elton B. Stephens Co. (EBESCO). Key search terms included: Pineal gland, melatonin and schizophrenia, pineal gland and schizophrenia, sleep and schizophrenia, melatonin and treatment for schizophrenia, alternative treatments for schizophrenia, and pineal volume and schizophrenia. Based on current researching findings, it is my prediction that the chief consensus among the literature will be that physiologic abnormalities often coincided with schizophrenia, but do not indicate the severity of the disease or seem to have a strong correlation to the cause of the disease. It is also my prediction that alternative therapies will be beneficial in reducing symptoms severity, and adverse effects cause by psychiatric medications.

No description available.

Investigamos o efeito do exercício físico no metabolismo do tecido adiposo e muscular de ratos pinealectomizados tratados ou não com melatonina. Foram retiradas amostras de sangue, tecido adiposo peri epididimal e músculo sóleo para testes biológicos. O treinamento físico mostrou-se eficiente através do aumento da velocidade máxima, atingida no final do treinamento, e da atividade da citrato sintase no músculo. A pinealectomia alterou o padrão de mobilização e utilização dos substratos pelos adipócitos e células musculares tornando menor a adaptação dos animais ao treinamento, causando um desajuste metabólico em vários parâmetros. Quando tratados com melatonina a adaptação funcional recuperou-se plenamente, tanto no tecido adiposo como muscular. Demonstrando que a glândula pineal tem um papel na regulação do metabolismo de lipídeos e carboidratos em resposta ao treinamento físico, a remoção da glândula causa alterações na resposta adaptativa do tecido adiposo e muscular e o tratamento com melatonina reverte o desajuste metabólico instaurado pela pinealectomia. / The current study investigated the effect of exercise on muscle and adipose tissue metabolism melatonin treated or non treated pinealectomized rats. Blood samples, peri-epididymal adipose tissue and soleus muscle were collected for biological tests. The physical training was efficient in increasing the maximum speed reached at the end of training, and the activity of citrate synthase in muscle. Pinealectomy changed the pattern of mobilization and utilization of substrates adipocytes and muscle cells decreasing the adjustment to the training in these animals, causing a mismatch in several metabolic parameters. When treated with melatonin, the functional adaptation is fully recovered both in adipose tissue and muscle. Demonstrating that the pineal gland has a role in regulating the metabolism of lipids and carbohydrates in response to physical training, the removal of the gland caused changes in the adaptive response of adipose tissue and muscle and the treatment with melatonin reversed the metabolic mismatch introduced by pinealectomy.

A doença de Chagas é um problema de saúde pública, com dados preocupantes do número de pessoas contaminadas e que ainda irão se contaminar. O objetivo desta investigação é avaliar o efeito da melatonina sobre o sistema imune na infecção chagásica experimental. Produzida pela glândula pineal possui várias ações fisiológicas, entre elas a mais importante, controlar o ritmo circadiano na grande maioria dos seres vivos. A melatonina foi administrada por via oral, tendo seu efeito avaliado através da quantificação dos níveis parasitêmicos, leucograma, histopatologia cardíaca e por ensaios imunológicos como IFN, TNF, IL-2, IL-12. A parasitemia foi drasticamente diminuída nos animais infectados e tratados com melatonina refletindo em uma diminuição ou quase ausência da presença de ninhos de amastigotas nas fibras cardíacas desses animais. A melatonina promoveu uma leucocitose com aumento dos neutrófilos e linfócitos. Não foi observada morte em nenhum dos grupos infectados tratados ou não com melatonina. Os ensaios imunológicos mostraram que as citocinas quantificadas apresentaram uma ação imunoestimuladora aumentada em relação aos grupos infectados que certamente foi responsável pela diminuição da carga parasitária sanguícola e tecidual. Dessa forma conclui-se que a melatonina exerceu um papel imunoestimulador importante, agindo sobre o eixo HHA que se refletiu em uma melhor resposta do hospedeiro durante o curso da infecção experimental. / Chagas disease is still considered a major problem in public health, with an alarming number of bearing parasite people and the risk of future contamination. The aim of this investigation is to evaluate a possible immunostimulatory effect of melatonin during the evolution of the experimental disease in Wistar rats infected with the Y strain of T. cruzi. Produced by pineal gland, it has a wide range of physiological functions, among them to control the circadian rhythm in most of the species. In this work melatonin was orally administrated being its effects evaluated by the number of blood trypomastigotes, leucogram, heart hystopathologyn and immunologic assays such IFN-, TNF-, Il-2, Il-12. Parasitemia was drastically reduced in melatonin treated infected animals consequently leading to a drop in the number of amastiogoter burdens being sacarcely found among heart fibers. Melatonin promoted a leucocytosis with enhanced levels of neutrophils and lymphocites. Absence of death was observed in all groups. Immuno-enhanced effects were observed with assays of IL-2, IL12, IFN- and TNF-. when compared to non treated animals. According to our data we conclude that Melatonin displayed an immunostimatory effect over the HHA axis, reducing blood and tecidual parasite consequently avoiding parasite replication during the evolution of the experimental infection in rats.

O objetivo geral da presente tese é testar a hipótese que a pineal faz parte integrante da resposta ao estresse, da mesma forma que está integrada ao processo inflamatório. Dois modelos de estresse, contenção e frio, foram aplicados aos ratos por 30 min ou 2 horas. Os resultados foram: ausência de úlceras gástricas e TNF em nível sérico por ambos os estresses, apenas aumento de corticosterona; somente em duas horas qualquer um dos estresses aumentou significativamente melatonina da pineal; tratamento tanto com metirapona como com mifepristone aboliram indistintamente os efeitos dos estresses; tratamento tanto com talidomida como com fenilefrina não modificaram os efeitos dos estresses. Concluímos que, o estresse moderado agudo, pela ação da corticosterona, promove modulação da pineal na dependência do estado fisiológico da mesma. Confirmamos a existência de uma relação entre as glândulas adrenais e pineal. Afirmamos que a glândula pineal exerce, além de suas clássicas funções cronobióticas, um papel de grande sensor do estado geral ao organismo inteiro. / The objective of this thesis is to test the hypothesis that the pineal is a player on stress response, likewise that it is one player in inflammatory process. Two stress models, restraint and cold, were applied to the rats for 30 min or 2 hous. The results were: absence of gastric ulcers and TNF serum levels in both stresses, just enhancement of corticosterone plasma levels; only in two hours anyone stress increased significantly pineal melatonin; metyrapone or mifepristone treatment abolish indistinctly the effects of the stresses; thalidomide or phenylephrine treatment did not modify the effects of the stresses. We conclude that the acute moderate stress by the corticosterone action promote modulation of pineal on the dependence of the physiological status of itself. We confirm the existence of a network between the adrenal and pineal glands. We affirm that the pineal gland performs, beyond of its chronobiotical classical functions, one role of the great sensor of internal body state to the whole organism.

A prevalência do diabetes mellitus tem aumentado exponencialmente, o estilo de vida noturna e o avanço na idade estão envolvidos neste mecanismo, influenciando também a produção de melatonina. O animal pinealectomizado apresenta resistência insulínica e redução na síntese de GLUT4. Mostramos que no músculo sóleo, houve um aumento na taxa de oxidação de glicose e síntese de glicogênio em todos os grupos treinados. Corroboramos com a literatura mostrando que o diabetes prejudica a sensibilidade da musculatura esquelética a ação da insulina. Tal evento, contudo, é corrigido pela suplementação com melatonina. A combinação destas terapias tem apresentado um efeito positivo do ponto de vista metabólico. / The prevalence of diabetes mellitus has increased, the nocturnal lifestyle and advancing age are involved in this mechanism, influencing the production of melatonin. The pinealectomized animal shows insulin resistance and reduced synthesis of GLUT4. Our results showed that in skeletal muscle (soleus) there was an increase in the rate of glucose oxidation and glycogen synthesis in all groups trained. Our data are consistent with the literature, showing that diabetes mellitus affect the sensitivity of skeletal muscle insulin action, reducing glucose uptake and glycogen synthesis. Nevertheless, this event is corrected by daily supplementation with melatonin. the combination of these therapies have shown a positive effect on metabolism.

Este estudo investigou o efeito protetor da melatonina sobre os danos ao DNA induzidos pela ciclofosfamida (20 e 50mg/kg) sobre as aberrações cromossômicas, fragmentação do DNA, ciclo celular e os sítios sensíveis a Fpg pelo Ensaio Cometa. Os níveis de RNAm de MGMT, p53, p21, Bax, Bcl-2, Top1, CSB e XPF foram analisados por qPCR. Após a remoção cirúrgica da glândula pineal, os animais foram tratados com 1 mg/kg de mel via oral durante 15 dias. Como resultados demonstramos que a melatonina foi capaz de reverter completamente o quadro de aberrações cromossômicas induzidas pela ciclofosfamida, indicando uma possibilidade de uso terapêutico quando da necessidade de uso de medicação quimioterápica. Esse quadro repetiu-se e ficou mais evidente com o estudo específico das lesões oxidativas pelo uso da Fpg. De todos os genes estudados, aquele que teve de forma mais consistente, sua expressão aumentada, sempre, pela melatonina foi XPF. Dessa forma, os mecanismos envolvidos com o reparo do DNA mobilizados pela melatonina parecem, em parte, mobilizar a expressão do gene XPF. / This study investigated the protetive effect of melatonin over DNA damage-induced by cyclophosphamide (20 and 50mg/kg) characterizing chromosomal aberrations, DNA fragmentation, cell cycle and determination of Fpg-sensitives sites by comet assay. The levels of MGMT, p53, p21, Bax, Bcl-2, Top1, CSB and XPF mRNA were examined by qPCR. After pineal gland surgical removal, animals were treated orally with 1 mg/kg of melatonin during 15 days. Results have shown that melatonin treatment was able to completelly revert chromossomal aberrations cyclophosphamide-induced, posssibly indicating a therapy use of melatonin in chemoterapic treatment. This effect was also demonstrated with the studies of oxidative lesions by Fpg-sensitives assay. From all studied genes, XPF showed the most increased expression. Thereby, DNA repair mechanisms triggered by melatonin, seems to mobilize XPF gene expression.

A síntese noturna de melatonina pela glândula pineal é inibida por padrões moleculares associados à patógenos ou à danos, como por exemplo lipopolissacarídeo (LPS) ou peptídeo &#946;-amilóide. A interação destas moléculas com receptores toll 4 (TLR4) ativa o eixo imune-pineal, favorecendo a migração de leucócitos para o local da injúria. Heparan sulfato (HS) é um glicosaminoglicano da matrix extracelular que por dano tecidual, inflamação generalizada ou migração de células tumorais, liberam dissacarídeos que podem ligar a TLR4, levando a formação de uma resposta inflamatória. Avaliamos se HS poderia prejudicar a atividade da melatonina. HS é capaz de inibir a síntese noturna de melatonina, através da supressão da expressão gênica e do conteúdo enzimático de acetilserotonina O-metiltransferase (ASMT). Este efeito é modulado pela interação de HS com TLR4, mas não envolve a via de translocação nuclear de NF-&#954;B. Estes dados sugerem que um aumento de moléculas de HS na matriz da glândula pineal é traduzido a todo o organismo por uma redução no pico noturno de melatonina. / The nocturnal synthesis of melatonin by the pineal gland is inhibited by pathogen or damage-associated molecular patterns, such as lipopolysaccharide (LPS) and &#946;-amyloid peptide. The interaction of these molecules with toll like receptors 4 (TLR4) activates the immune-pineal axis, favoring the migration of leukocytes for the site of lesion. Heparan sulfate (HS), a glycosaminoglycan of the extracellular matrix, that in case of tissue injury, generalized inflammation or migration of tumor cells, releases disaccharide, which can bind to TLR4 triggering an inflammatory response. Here we evaluated if HS could impair nocturnal melatonin activity. HS is capable of inhibit the melatonin synthesis by the suppression of the gene expression and enzymatic content of acetylserotonin O-methyltransferase (ASMT). This effect is modulated by the interaction of HS with TLR4, but does not involve the NF-&#954;B nuclear translocation pathway. This data suggest that the increase in HS in pineal gland matrix is translated to the whole organism by a reduction in the nocturnal melatonin peak.