Hormones: 2012

Tuesday, December 4, 2012

Serotonin

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter derived from tryptophan, primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS). In Gut, serotonin regulates intestinal movements, in CNS, it regulates mood, appetite, sleep, memory and learning, etc.
1. Brain serotonin, carbohydrate-craving, obesity and depression
Serotonin-releasing brain neurons are unique in that the amount of neurotransmitter they release is normally controlled by food intake, according to the study by Massachusetts Institute of Technology, Cambridge serotonin release is also involved in such functions as sleep onset, pain sensitivity, blood pressure regulation, and control of the mood. Hence many patients learn to overeat carbohydrates (particularly snack foods, like potato chips or pastries, which are rich in carbohydrates and fats) to make themselves feel better. This tendency to use certain foods as though they were drugs is a frequent cause of weight gain, and can also be seen in patients who become fat when exposed to stress, or in women with premenstrual syndrome, or in patients with "winter depression," or in people who are attempting to give up smoking. (Nicotine, like dietary carbohydrates, increases brain serotonin secretion; nicotine withdrawal has the opposite effect.) It also occurs in patients with normal-weight bulimia. Dexfenfluramine constitutes a highly effective treatment for such patients. In addition to producing its general satiety-promoting effect, it specifically reduces their overconsumption of carbohydrate-rich (or carbohydrate-and fat-rich) foods(1).

2. Brain serotonin in excessive carbohydrate snacking craving
Brain neurotransmitter serotonin plays an essential role in a specific hunger for carbohydrate-rich foods in animals and human beings, researchers found that consumption of a carbohydrate-rich meal increases the synthesis and release of brain serotonin (by enhancing the brain uptake of its precursor, tryptophan). As a consequence of this increased release of serotonin, carbohydrate intake is decreased at the next meal. Consumption of protein does not increase brain serotonin levels or decrease carbohydrate intake. A subgroup of obese individuals who consume carbohydrate-rich snack foods at specific times of day or evening has been identified. Such individuals do not routinely snack on protein-rich foods, and their consumption of calories and nutrients at meals is not excessive. Evidence is presented that carbohydrate snacking seems to be related to a "need" to increase the level of brain serotonin; treatment with a drug, d-1 fenfluramine, that increases serotoninergic neurotransmission significantly decreases carbohydrate snack consumption. Weight loss among the population of carbohydrate cravers might be most successful if treatment includes either a diet or drugs that increase brain serotonin activity when the need to snack on carbohydrate is most likely to occur(2).

3. Changes in mood after carbohydrate consumption
In the study to identify two groups of obese individuals who consume excessive calories primarily as snack foods, found that using standardized self-report questionnaires, we measured mood before and 2 h after consumption of a high-carbohydrate lunch (104 g CHO). Responses to the meal differed significantly: noncarbohydrate cravers reported feeling considerably less alert, more fatigued and sleepy, while carbohydrate cravers described little or no change in these aspects of mood.(3)

4. Mood and carbohydrate cravings
In the study to investigate a sample of 113 males and 138 female college students of the relationship between mood and carbohydrate cravings, and the possible role of gender in these associations, found that individuals classifying themselves as "carbohydrate cravers" reported foods rich in carbohydrates, and "protein cravers" reported protein-rich foods as being the ones they most strongly craved. Carbohydrate cravers reported feeling distressed prior to their cravings and satisfied, happy/good and relaxed following carbohydrate consumption. Protein cravers reported feeling anxious or hungry prior to their cravings and happy, normal, bored, and energetic following protein-rich food consumption(4).

5. Effects of protein and carbohydrate meals on mood and performance: interactions with sex and age
In the study to investigate the normal adult subjects (n = 184) consumed a high-protein or high-carbohydrate meal and were tested two hours later their mood and performance, found that females, but not males, reported greater sleepiness after a carbohydrate as opposed to a protein meal. Male subjects, but not females, reported greater calmness after a carbohydrate as opposed to a protein meal. When meals were eaten for breakfast (but not for lunch) individuals 40 yr of age or older felt more tense and less calm after a protein than after a carbohydrate meal. Although older subjects reported subjective discomfort after a morning protein meal, they displayed objective performance impairments after a carbohydrate lunch. Subjects 40 yr of age or older were impaired on a test of sustained selective attention (dichotic shadowing) after consuming a high-carbohydrate lunch(5).

6. Mood, performance, and pain sensitivity: changes induced by food constituents
In the study to examine the behavioral effects of the dietary constituents tryptophan and tyrosine on human mood, sensorimotor performance and pain sensitivity, found that tryptophan and tyrosine are neurotransmitter precursors present in varying amount in protein-containing foods. Tryptophan (50 mg/kg) increased subjective drowsiness and fatigue but unlike many hypnotics did not impair sensorimotor performance. Tryptophan also decreased human pain sensitivity in a manner that was more specific than certain analgesic drugs(6).

7. Effects of dietary neurotransmitter precursors on human behavior
In a double-blind, crossover study the possible effects of tryptophan and tyrosine on human behavior, single oral doses of these substances and matched placebos were administered to 20 men, found that
tryptophan increased subjective fatigue and decreased self-ratings of vigor and alertness, but did not impair performance on any of the tests. Tyrosine produced no effects in our young population compared with placebo, but did decrease reaction time relative to tryptophan. It may be concluded that tryptophan has significant sedative-like properties, but unlike other sedatives may not impair performance(7).

8. Serotonin: influences on male sexual behavior
Serotonin (5-HT) is primarily inhibitory, although stimulation of 5-HT(2C) receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT(1A) receptors has the opposite effects: facilitation of ejaculation and, in some circumstances, inhibition of erection. 5-HT is released in the anterior lateral hypothalamus at the time of ejaculation. Microinjections of selective serotonin reuptake inhibitors there delay the onset of copulation and delay ejaculation after copulation begins, according to the study by State University of New York(8).

9. Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems
In the study to review the neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions, showed that Estrogen alone, or in combination with progesterone, affects the brain serotonin system differently in different parts of the brain, which can at least partly explain the opposite effects on mood of those hormones. Many of the progesterone effects in the brain are mediated by its metabolite allopregnanolone. Allopregnanolone, by changing GABA(A) receptor expression or sensitivity, is involved in premenstrual mood changes; and it also induces cognitive deficits, such as spatial-learning impairment(9).

10. Serotonin, aging and cognitive functions
Serotonin and acetylcholine interact to allow normal cognitive functions in the brain. Thus, a partial reduction in both cholinergic and serotonergic functions will cause severe memory impairment in young as well as in aged rats, according to the dtudy by Department of Neurobiology, Weizmann Institute(10).

11. Serotonin circuits and anxiety
Fear, a reaction to a threatening situation, is a broadly adaptive feature crucial to the survival and reproductive fitness of individual organisms. By contrast, anxiety is an inappropriate behavioral response often to a perceived, not real, threat. In the study by The Salk Institute for Biological Studies functional imaging, biochemical analysis, and lesion studies with humans have identified the HPA axis and the amygdala as key neuroanatomical regions driving both fear and anxiety. Abnormalities in these biological systems lead to misregulated fear and anxiety behaviors such as panic attacks and post-traumatic stress disorders. These behaviors are often treated by increasing serotonin levels at synapses, suggesting a role for serotonin signaling in ameliorating both fear and anxiety. Interestingly, serotonin signaling is highly conserved between mammals and invertebrates(11).

12. Serotonin in Alzheimer's disease
Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. In the study by Northeast Ohio Medical University researchers indicated that as a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. While many of these compounds will likely find application as adjuvant therapy in the symptomatic treatment of Alzheimer's disease, there are currently only a few drug entities with activity against serotonin receptors that may offer the potential to alter the progression of the disease(12).

13. Biosynthesis and the development of Parkinson's disease and schizophrenia

In the study of Somatic transposition in the brain influences the biosynthesis of metabolites involved in Parkinson's disease and schizophrenia, researcher shows that somatic transposition in the human brain can influence the biosynthesis of more than 250 metabolites, including dopamine, serotonin and glutamate, shows large inter-individual variability in metabolic effects, and may contribute to the development of Parkinson's disease and schizophrenia.

14. Serotonin and vasoconstrictor synergism
In the study to observe the Contractile synergism between serotonin (5-hydroxytryptamine, 5-HT) and other vasoconstrictor substances in a number of peripheral and cerebrovascular blood vessels, found that this phenomenon may play an important role in certain pathological states such as hypertension, peripheral vascular disease, and coronary spasm. Tthe synergism between serotonin and other vasoconstrictor agents and focus on a recently described type of vasoconstrictor synergism in which precontraction with a non-5-HT receptor agonist yields an enhanced contractile response to serotonin which is mediated by previously inactive or "silent" 5-HT receptor subtypes(14).

15. Serotonin and arterial vessels
The vasodilator effects of serotonin can be caused by (a) inhibiting vascular smooth muscle directly, (b) releasing other inhibitory substances, such as vasoactive intestinal polypeptide, (c) inhibiting adrenergic neurotransmission, and (d) triggering of endothelium-dependent relaxation, according to the study by J Cardiovasc Pharmacol. 1984;6 Suppl 2:S421-8(15).

16. Serotonin and vascular reactivity
In the study of Serotonin causes of contraction of the vascular smooth muscle cells in most blood vessel, found that at low concentrations serotonin amplifies the vasoconstrictor responses to other vasoactive substances. Ultimately the effect of serotonin on vascular constriction is defined by the balance between these different actions. In the intact organism under normal conditions serotonin may play a modulatory role but exacerbation of the contractile effects because of hypersensitivity of the smooth muscle cells, local physical or humoral factors or loss of the relaxatory ability may lead to abnormal tissue responses. Thus, serotonin-induced vasoconstrictor responses may play a role in the etiology of vasospasm and peripheral vascular diseases, in particular at sites of endothelial lesions(16).

17. Serotonin and the blood vessel wall
Serotonin has complex effects on the cardiovascular system. In the intact animal it may cause increases or decreases of blood pressure and in isolated blood vessels contraction or relaxation depending on the species and vascular bed studied, the route of administration and the dosage used. According to the study by Dr. Vanhoutte PM and Dr. Lüscher TF. serotonin may act indirectly by amplifying the response to norepinephrine and other agonists, by displacing norepinephrine from adrenergic nerve terminals or releasing constrictor substance(s) from the endothelium. Dilatation in response to serotonin is mediated by endothelial and prejunctional S1-serotonergic receptors which pharmacologically resemble 5-HT1-binding sites. In hypertension, constrictor responses to serotonin are augmented, while the vasodilator effects of the monoamine are decreased. The constrictor response to serotonin is increased more than those to other agonists, suggesting a functional rather than a structural adaptation of the hypertensive blood vessel wall. In hypertension the turnover of circulating platelets, the major source of peripheral serotonin, is accelerated and the mechanisms for the removal of the monoamine are impaired. The functional changes of the blood vessel wall and platelets could play a role in the maintenance of the increased peripheral vascular resistance in chronic hypertension, and they could be involved in the pathogenesis of complications of the hypertensive process(17).

18. Cardiovascular effects of serotonin
Serotonin causes contraction of most large arteries and veins; it also causes contraction of venules. This is due mainly to direct activation of vascular smooth muscle, although amplification of the response to other endogenous vasoconstrictors (e.g., angiotensin II and norepinephrine) as well as facilitated release of norepinephrine may contribute. In peripheral blood vessels, the receptors mediating the contractions evoked by serotonin belong mainly to the 5-HT2-serotonergic subtype; in the coronary and cerebral arteries, this need not be the case. Vasodilator responses to serotonin are seen mainly at the arteriolar level, but they can also be observed in larger blood vessels. They can be caused by the release of other endogenous vasodilators (e.g., vasoactive intestinal polypeptide), direct relaxation of vascular smooth muscle, inhibition of adrenergic neurotransmission, or production of endothelium-derived relaxing factor(s). The dilator responses to serotonin are mediated by receptors with characteristics similar to 5-HT1-serotonergic binding sites. Aggregating platelets release enough serotonin to evoke both constrictor and dilator responses. The absence of endothelium may change the primary response to aggregating platelets from relaxation to contraction. The responsiveness of the blood vessel wall to serotonin can be augmented acutely by local hypoxia or by cooling(18).

19. Correction of altered serotonin exchange in adolescents with functional disorders of digestive system
In the searching for the ways of improvement treatment of functional pathologies of the system of digestion an author is studied the concentration and the role of serotonin in 180 adolescents, showed that serotonin receptors 5HT1 agonists were used for patients with paroxysms of abdominal pain mainly at neurocirculatory disfunction and migraine(19).

20. Serotonin and Fibromyalgia and migraine
In the study of fibromyalgia sufferers randomly administered a combination of monoamine-oxidase inhibitors (MAOIs)-A/B with 5-HTP, 5-HTP alone, MAOIs-A/B alone, or the tricyclic drug amitriptyline in order to compare the efficacy of these treatments, showed that high prevalence of migraine in the population of fibromyalgia sufferers, suggests a common ground shared by fibromyalgia and migraine. Migraine has been demonstrated to be characterized by a defect in the serotonergic and adrenergic systems. A parallel dramatic failure of serotonergic systems and a defect of adrenergic transmission have been evidenced to affect fibromyalgia sufferers too. Enhancing serotonergic analgesia while increasing adrenergically mediated analgesia seems to be an important tool in fibromyalgia(20).

21. Serotonin in the regulation of emotion processing and mood
Monoamines, such as serotonin, dopamine, and norepinephrine, play a crucial role in the regulation of emotion processing and mood. In the study to investigate how polymorphisms of the serotonin transporter (5-HTT) and catechol-O-methyltransferase (COMT) influence emotion recognition abilities, researchers at the Department of General Psychiatry, Innsbruck Medical University, found that s-allele carriers performed significantly worse in the recognition of happy faces, but did better in the recognition of fearful faces, compared with homozygous l-carriers of the 5-HTT gene. Neither 5-HTT nor COMT genotypes influenced the ability to discriminate between different intensities of sadness or happiness on the PEAT(21).

22. Hemostasis, platelet function and serotonin in acute and chronic renal failure
In the study to investigate some fibrinolytic parameters and platelet function of 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF), found that since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure(22).

23. Platelet functions, some hemostatic and fibrinolytic parameters in relation to serotonin
Erythropoietin corrects anemia and improves hemostasis, but on the other hand bears a risk of thrombotic complications. In the study to evaluate bleeding time, platelet functions and some hemostatic and fibrinolytic parameters in relation to blood and platelet serotonin before and after 1, 2, 4, 8 and 12 weeks of treatment in 22 chronically hemodialyzed patients were administered with human recombinant erythropoietin (rHuEPO) in a dose of 2000 IU s.c. 3 times a week, showed that rHuEPO may improve platelet/vessel wall interactions possibly by means of serotonergic mechanisms. A lowered activity of inhibitors of fibrinolysis may be regarded as a protection against a general tendency to thrombosis during rHuEPO therapy(23).

24. Serotonin and carcinoid
There is a report of a 66-year-old woman was diagnosed with hepatic metastasized carcinoid tumor of the ileocecal junction resulting in elevated plasma chromogranin A levels and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Further examination showed right-sided heart failure with severe tricuspid valve regurgitation. Carcinoid tumors produce serotonin which leads to flushing, secretory diarrhea, bronchospasm and hypotension, known as carcinoid syndrome. Serotonin is metabolized to 5-HIAA, which is inactive, in the liver and the lungs(24).

25. Serotonin and Substance abuse
Serotonin (5-hydroxytryptamine [5-HT]) is an important neurotransmitter implicated in regulating substance-use disorder (SUD) acquisition, maintenance, and recovery. According to the VA Connecticut Healthcare/Yale University School of Medicine, During the past several years, an abundance of research has begun discovering and describing specific 5-HT genetic polymorphisms associated with SUDs. Genetic variations in the 5-HT system, such as SLC6A4, HTR1B, HTR2A, HTR2C, HTR3 (HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E), likely play a role contributing to SUD patient heterogeneity(25).

26. Serotonin and the severity of alcohol drinking
Severe drinking can cause serious morbidity and death. In a double-blind controlled trial randomized 283 alcoholics by genotype in the 5'-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3'-untranslated region, showed that Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5'-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined(26).

27. Serotonin and Autism
Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. In the study to test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, by analyzing mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder, found that mice lacking brain serotonin (TPH2-/-) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2-/- mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism(27).

28. Serotonin and severity of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms.
In the study to examine the association between a common serotonin transporter gene (SLC6A4) polymorphism 5-HTTLPR/rs25531 with severity of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms, researchers at the Department of Psychiatry and Behavioral Sciences, Stony Brook University, showed that the 5-HTTLPR/rs25531 polymorphism or its correlates may modulate severity of ADHD and ASD symptoms in children with ASD, but in different ways. These tentative, hypothesis-generating findings require replication with larger independent samples(28).

29. Serotonin and sexual desire disorders
Hypoactive sexual desire disorder (HSDD) is thought to be the most prevalent form of female sexual dysfunction (FSD), affecting up to 1 in 10 US women. Hypoactive sexual desire disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders, showed that Causes of low desire include chronic medical conditions, medications, surgeries, and psychosocial factors, but not necessarily increased age; both pre- and postmenopausal women can have HSDD, although the frequency appears to vary by age. Sexual function requires the complex interaction of multiple neurotransmitters and hormones, both centrally and peripherally, and sexual desire is considered the result of a complex balance between inhibitory and excitatory pathways in the brain. For example, dopamine, estrogen, progesterone, and testosterone play an excitatory role, whereas serotonin and prolactin are inhibitory. Thus, decreased sexual desire could be due to a reduced level of excitatory activity, an increased level of inhibitory activity, or both. A number of validated self-report and clinician-administered instruments are available for assessing female sexual function; however, most have been used primarily in clinical research trials(29).

30. Monoamine deficiency and relative nutritional deficiency
In the study to to demonstrate that the primary component of chronic centrally acting monoamine (serotonin, dopamine, norepinephrine, and epinephrine) disease is a relative nutritional deficiency induced by postsynaptic neuron damage, showed that humans suffering from chronic centrally acting monoamine-related disease are not suffering from a drug deficiency; they are suffering from a relative nutritional deficiency involving serotonin and dopamine amino acid precursors. Whenever low or inadequate levels of monoamine neurotransmitters exist, a relative nutritional deficiency is present. These precursors must be administered simultaneously under the guidance of monoamine transporter optimization in order to achieve optimal relative nutritional deficiency management. Improper administration of these precursors can exacerbate and/or facilitate new onset of centrally acting monoamine-related relative nutritional deficiencies(30).

31. Monoamine and diseases
The monoamine hypothesis has been recognized for over half a century as a reference point to understanding electrical dysfunction associated with disease states, and/or regulatory dysfunction related to synaptic, centrally acting monoamine concentrations (serotonin, dopamine, norepinephrine, and epinephrine). According to the study by the Clinical Research, Neuro Research Clinics, centrally acting monoamine concentrations are indistinguishable in subjects with and without disease symptoms and/or regulatory dysfunction. Analysis of centrally acting monoamine concentrations in the endogenous state reveals a significant difference in day-to-day assays performed on the same subject with and without monoamine-related disease symptoms and/or regulatory dysfunction(31).

32. Metabolic syndrome: a brain disease
According to the study by The TsimTsoum Institute, Krakow, Silesia, Poland, increased sympathetic activity, with increased secretion of catecholamine, cortisol, and serotonin can cause oxidative stress, which may damage the arcuate nucleus as well as the hypothalamus and macrophages, and the liver may release pro-inflammatory cytokines. These, in conjunction with an underlying deficiency in long chain PUFA, may damage the arcuate nucleus as well as neuropeptide-Y and pro-opiomelanocortin neurons and insulin receptors in the brain, especially during fetal life, infancy, and childhood, resulting in their dysfunction(32).

33. Elevated 5-HT (serotonin) levels in early postnatal life and autism spectrum disorders (ASDs)
In the study to examine two inbred mouse strains (C57BL/6 and BALB/c) with respect to these phenomena of transient brain overgrowth in early postnatal life and elevated 5-HT (serotonin) levels in blood platelets (platelet hyperserotonemia). The BALB/c strain is less social and exhibits some other autistic-like behaviors, found that in mice, autistic-like shifts in the brain and periphery may be associated with less autistic-like behaviors. Importantly, they suggest that consistency among behavioral, anatomical, and physiological measures may expedite the validation of new and previously proposed mouse models of autism, and that the construct validity of models should be demonstrated when these measures are inconsistent(33).

34. Carcinoid Heart Disease and high levels of Serotonin
In the study to review our experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiogram) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principal metabolite, showed that study reviews our experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiogram) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principal metabolite(34).

35. Serotonin neurotransmission in anorexia nervosa
Patients with anorexia nervosa (AN) show extreme dieting weight loss, hyperactivity, depression/anxiety, self-control, and behavioral impulsivity. 5-Hydroxytryptamine (5-HT; serotonin) is involved in almost all the behavioral changes observed in AN patients. According to the study by University of Karachi, Karachi, diet restriction-induced exaggerated feedback control over 5-HT synthesis and the smaller availability of tryptophan decreases serotonin neurotransmission at postsynaptic sites, leading to hyperactivity, depression, and behavioral impulsivity. A compensatory upregulation of postsynaptic 5-HT-1A receptors and hypophagic serotonin receptors may be involved in anxiety and suppression of appetite(35).

36. Obesity, whole blood serotonin and sex differences in healthy volunteers
In the study of healthy adult volunteers (N = 68) who gave whole blood samples for measurement of WB serotonin, and underwent BMI waist circumference (WC) and waist-to-hip ratio (WHR) assessment as well as DEXA (dual energy X-ray absorptiometry) scans for anthropometric parameters, showed that for the whole sample, WB serotonin was significantly negatively correlated with BMI, WC, WHR as well as android, gynoid and total % body fat. Analysis by sex showed significant negative correlations between WB serotonin and android, gynoid as well as total fat in males, but not in females(36).

37. Serotonin and wound healing
The molecule serotonin (5-hydroxytryptamine or 5-HT) is involved in numerous biological processes both inside and outside of the central nervous system. 5-HT signals through 5-HT receptors and it is the diversity of these receptors and their subtypes that give rise to the varied physiological responses. It is clear that platelet derived serotonin is critical for normal wound healing in multiple organs including, liver, lung heart and skin, according to the study by William Leech Building, Newcastle University(37)

38. Tryptophan depletion affects heart rate
In a a randomized, counterbalanced, double-blind crossover design study, nineteen patients in remission from depression received high-dose and low-dose acute tryptophan depletion, found that high-dose acute tryptophan depletion led to a larger increase in depressive symptoms than did low-dose acute tryptophan depletion. High-dose acute tryptophan depletion decreased heart rate variability and increased impulsivity and anxiety, but only in patients with a history of suicidal ideation. Symptom effects of high-dose acute tryptophan depletion correlated with low heart rate variability at baseline(38).

39. Serotonin and insulin resistance
In the study to assess the effect of 5-HT on insulin-mediated glucose uptake, showed that the effects of 5-HT on insulin-mediated glucose uptake were partially reversed by vasodilation with carbachol. In contrast to the results for the hindlimb, 10 microM 5-HT had no significant effect on either basal glucose uptake or the stimulation of glucose uptake mediated by 15 nM insulin by isolated incubated soleus or extensor digitorum longus muscles. It is concluded that 5-HT impairs insulin-mediated glucose uptake in the perfused rat hindlimb that may derive from vascular shunting not apparent when muscles are incubated with 5-HT in vitro(39).

40. Serotonin and type 2 diabetes
In the study of the serotonin 2C receptor (5-HT(2C)R) agonists for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes, found that 5-HT(2C)R agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs(40).

41. Serotonin and irritable bowel syndrome with diarrhea
In a biopsy specimens evaluation to assess the inflammation, enterochromaffin cell numbers, 5-HT content, and messenger RNA (mRNA) levels for the synthetic enzyme, tryptophan hydroxylase 1, and the serotonin transporter (SERT) by quantitative real-time reverse-transcription polymerase chain reaction, indicated that the role of 5-HT signaling in IBS in children and argue against such a role in FD(41).

42. 5-HT(1A) receptors and lower urinary tract function and 'fight-or-flight' conditions
In the study to examine the role of 5-HT(1A) receptors in control of lower urinary tract function in cats, using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) as agonists and WAY100635 and LY206130 as antagonists, found that 5-HT(1A) receptor stimulation is inhibitory to bladder function in cats, especially under conditions where the bladder is hyperactive due to irritation. Furthermore, these bladder-inhibitory effects are the exact opposite of the bladder-excitatory effects of 8-OH-DPAT reported in rats. 5-HT(1A) receptor stimulation increases EUS motoneuron activity when driven by nociceptive bladder afferent inputs but not when driven by non-nociceptive afferent inputs. In summary, 5-HT(1A) receptor agonists facilitate a nociceptor-driven spinal reflex (sphincter activity) but inhibit a nociceptor-driven supraspinal reflex (micturition). This pattern of activity would facilitate urine storage and may be important under 'fight-or-flight' conditions when serotonergic activity is high(42).

43. Neuronal serotonin regulates growth of the intestinal mucosa
5-HT promotes growth and turnover of the intestinal mucosal epithelium. Surprisingly, these processes appear to be mediated by neuronal, rather than mucosal, 5-HT. The 5-HT(2A) receptor activates cholinergic neurons, which provide a muscarinic innervation to epithelial effectors, according to teh study by College of Physicians and Surgeons, Columbia University(43)

44. Serotonin and reproduction
Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. In the study of oral administration to female CD rats (20/group) at doses of 0, 3, 10, or 30 mg/kg to evaluate effects on mating, fertility, litter size, live birth index (100 x total liveborn progeny/litter size), progeny survival, and weight gain of each litter, found that on postpartum day 8, progeny in the control, 30 mg/kg and 30 mg/kg recovery groups were removed from dams for 4 h. Progeny were weighed as litters, returned to the dams for a 1-h nursing period, and then weighed again to provide an indication of milk intake. Mating and fertility, using the present study design, were not affected by treatment with amesergide. No effects were observed on litter size, live birth index, or progeny survival. In contrast, treatment with amesergide throughout gestation and lactation produced a significant dose-related depression in progeny body weight gains(44).

45. Serotonin and aging
In the study to assess Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life and its contribution to behavioral changes commonly observed in the elderly population, found that there is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life(45).

46. The role of serotonin in the regulation of bone metabolism

In the brain, brain derived serotonin regulates bone mass through sympathetic nervous system. In addition, inhibition of GDS biosynthesis can treat osteoporosis in ovariectomized rodents by increasing bone formation. The emerging evidence has suggested that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis in humans, according to thye study by Department of Genetics and Development, Columbia University(46).

47. N-acetyl serotonin and neuroprotectants for retinas
N-acetylserotonin (NAS) is synthesized from serotonin by arylalkylamine N-acetyltransferase (AANAT), which is predominantly expressed in the pineal gland and retina. Researchers at the Emory University School of Medicine, found that he compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases(47).

48. Serotonin and inflammatory pain
In the study to investigate the reverse transcriptase polymerase chain reaction (RT-PCR) technique used to examine the changes of the expression of 5-hydroxytryptamine (5-HT) receptors in the rat lumbar dorsal root ganglion (DRG) following subcutaneous bee venom (BV) injection into the plantar surface of the unilateral hindpaw, showed that the different sets of 5-HT receptor subtypes work at different stages of the inflammatory pain induced by subcutaneous BV injection(48).

49. Serotonin and life span
In the study to develop a new quantitative method to analyze Caenorhabditis elegans behavioral states, found that the proportion of time spent in each state is modulated by past nutritional experiences of the animal. This two-state behavior is regulated through serotonin as well as insulin and TGF-beta signaling pathways. Biogenic amines signaling could allow the worm to adapt to fast changes in the environment when peptide transcriptional pathways may mediate slower adaptive changes(49).

50. Fetal serotonin signaling: setting pathways for early childhood development and behavior
Finely tuning levels of the key neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) during early life is essential for brain development and setting pathways for health and disorder across the early life span. Understanding the impact of early changes in serotonergic programming offers critical insights that might explain patterns of individual differences in developmental risk and resilience, according to the study by Child and Family Research Institute(50).

Wednesday, November 14, 2012

Melatonin (N-acetyl-5-methoxytryptamine)

Melatonin, also known as N-acetyl-5-methoxytryptamine, a hormone secreted by the pineal gland in the brain with functions of regulating sleep cycles, other hormones, timing in secretion of female hormones that affect the menstrual cycle, etc. The levels of the circulating hormone vary in a daily cycle, depending to the circadian rhythm is an internal 24-hour “clock”.

1. Melatonin as an antioxidant
One important feature, as a role as a pervasive and powerful antioxidant, Melatonin protect our body from free radicals by fighting against damage of the nuclear and mitochondrial DNA of the cells. In a study of "Free Radical-Mediated Molecular Damage Mechanisms for the Protective Actions of Melatonin in the Central Nervous System" by RUSSEL J. REITER, DARIO ACUÑA-CASTROVIEJO, DUN-XIAN TAN and SUSANNE BURKHARDT, researchers concluded that most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

2. Melatonin (N-acetyl-5-methoxytryptamine) and Headaches
Over counter melatonin supplement has been proven to be effectively prevent and treat migraines and headaches. In a study of The therapeutic potential of melatonin in migraines and other headache types by Gagnier JJ., researcher found that melatonin may play a role in resynchronizing biological rhythms to lifestyle and subsequently relieve migraines and other forms of headaches. In addition, research testing the administration of melatonin found it safe in migraine sufferers, with few or no side effects. However, a larger, randomized control trial is needed to definitively determine if administration of melatonin to migraine patients is effective.

3. Melatonin (N-acetyl-5-methoxytryptamine) and Circadian disturbances
According to the article of Is Internal Timing Key to Mental Health? Published by AAAS, the article indicated that... psychiatrists working with small groups of patients have shown that
correcting abnormal circadian rhythms—through exposure to light, melatonin pills, or even sleep deprivation—can help treat some of these disorders,....

4. Melatonin (N-acetyl-5-methoxytryptamine) and Depression associated with the menopause
According to the study of "Effects of Melatonin in Perimenopausal and Menopausal Women: Our Personal Experience" by Bellipanni G, DI Marzo F, Blasi F, Di Marzo A., researchers concluded that At present we assert that the six-month treatment with MEL produced a remarkable and highly significant improvement of thyroid function, positive changes of gonadotropins towards more juvenile levels, and abrogation of menopause-related depression.

5. Melatonin (N-acetyl-5-methoxytryptamine) and Prolactin
In a study of Evening administration of melatonin enhances the pulsatile secretion of prolactin but not of LH and TSH in normally cycling women, by Massimo Terzolo, Alberto Revelli, Daniela Guidetti, Alessandro Piovesan, Paola Cassoni, Piero Paccotti, Alberto Angeli, Marco Massobrio, researchers found that Exogenous melatonin has a stimulatory effect on PRL release without affecting the temporal pattern of its pulsatile secretion in normal women. Melatonin has minor, if any, effect on TSH secretion whereas the effect on LH may depend on individual sensitivity.

6. Melatonin (N-acetyl-5-methoxytryptamine) and Fertility
Melatonin can enhance fertility of a woman by lowering Follicle stimulating hormones, according to the article of "You should know about Melatonin and Fertility" by Dr. Tanya Smith, TCM, ... at the 20th World Congress on Fertility and Sterility in September 2010 and found that the fertilization rate among women who took 3 mg tablets of melatonin (n = 56) during the second IVF cycle were improved compared with those achieved during their first failed cycle, at 50.0% versus 20.2%. Patients who did not take melatonin (n = 59) experienced no change in fertilization rates.

7. Melatonin (N-acetyl-5-methoxytryptamine) and Menopause
In a study of "Decrease in melatonin precedes follicle-stimulating hormone increase during perimenopause" Olli Vakkuri, Aarre Kivelä, Juhani Leppäluoto, Maija Valtonen and Antti Kauppila, researchers found that the inverse changes in melatonin and FSH secretion during the perimenopausal years, with the sharpest decline in nocturnal excretion of melatonin far before menopause, suggest that melatonin may be permissively linked to the initiation of menopause.

7. Melatonin (N-acetyl-5-methoxytryptamine) and Anxiety: the association with lower melatonin levels
In a study of "Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance" by Acil M, Basgul E, Celiker V, Karagöz AH, Demir B, Aypar U., researchers concluded that Melatonin premedication was associated with preoperative anxiolysis and sedation without postoperative impairment of psychomotor performance.

8. Anti-depressant action of melatonin
In the study to investigate the antidepressant effect of physiological and pharmacological doses of melatonin in the Porsolt forced swimming-induced behavioral despair test, showed that acute administration of higher doses of melatonin (2.5-10 mg/kg) failed to induce any anti-depressant activity in mice which were subjected to forced swimming test for the first time. However, daily administration of melatonin (2.5-10 mg/kg) prior to swimming test significantly reversed the increase in immobility period that was observed on chronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAergic drugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test(8).

9. Direct involvement of melatonin in modulation of ovarian steroidogenesis
In the study to investigate the gene expression of the two different forms of melatonin receptors in human granulosa-luteal cells, using RT-PCR. PCR products corresponding to the expected sizes of the melatonin receptor subtypes, mt(1)-R and MT(2)-R, which were obtained from granulosa-luteal cells, and the authenticity of the PCR products was confirmed by Southern blot hybridization with cDNA probes, showed that melatonin treatment alone had no effect on basal progesterone production but enhanced the effects of human CG-stimulated progesterone production. Because MAPKs are activated in response to a diverse array of extracellular stimuli leading to the regulation of cell growth, division, and differentiation, and because melatonin has been shown to modulate cellular proliferation and differentiation. But melatonin activated MAPK in a dose- and time-dependent manner can regulate progesterone production, LH receptor, GnRH, and GnRH receptor gene expression through melatonin receptors in human granulosa-luteal cells, which may be mediated via the MAPK pathway and activation of Elk-1(9).

10. Tryptophan-enriched cereal intake in elderly humans
In the study to analyze whether the consumption of cereals enriched with tryptophan, the precursor of both serotonin and melatonin, may help in the reconsolidation of the sleep/wake cycle and counteract depression and anxiety in 35 middle-aged/elderly (aged 55-75 year) volunteers in a simple blind assay, showed that the consumption of cereals containing the higher dose in tryptophan increased sleep efficiency, actual sleep time, immobile time, and decreased total nocturnal activity, sleep fragmentation index, and sleep latency. Urinary 6-sulfatoxymelatonin, 5-hydroxyindoleacetic acid levels, and urinary total antioxidant capacity also increased respectively after tryptophan-enriched cereal ingestion as well as improving anxiety and depression symptoms. Cereals enriched with tryptophan may be useful as a chrononutrition tool for alterations in the sleep/wake cycle due to age(10).

11.Melatonin and circadian rhythms and sleep
melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. In the study of Role of melatonin in the regulation of human circadian rhythms and sleep, researchers found that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time(11).

12. Melatonin in the treatment of cancer
In a systematic review of randomized controlled trials between 1992 and 2003 and included 643 patients. All trials included solid tumor cancers. All trials were conducted at the same hospital network, and were unblinded. Melatonin reduced the risk of death at 1 yr (relative risk: 0.66, 95% confidence interval: 0.59-0.73, I2=0%, heterogeneity P<or=0.56). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported, according to the report of the Department of Clinical Epidemiology, McMaster University(12). Others suggested that Melatonin is effective in suppressing neoplastic growth in a variety of tumors like melanoma, breast and prostate cancer, and ovarian and colorectal cancer. As an adjuvant therapy, melatonin can be beneficial in treating patients suffering from breast cancer, hepatocellular carcinoma or melanoma(12a).

13. Melatonin in oral health and disease
According to the study of Faculty of Dentistry, Zonguldak Karaelmas University, melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers(13). Other researchers suggested that strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer's disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2(14). Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions(15).

16. Melatonin and cancer theapies
In the searched 7 databases: MEDLINE (1966-February 2010), AMED (1985-February 2010), Alt HealthWatch (1995-February 2010), CINAHL (1982-February 2010), Nursing and Allied Health Collection: Basic (1985-February 2010), the Cochrane Database (2009), and the Chinese database CNKI (1979-February 2010). They included all trials that randomized patients to treatment, including MLT or a similar control group without MLT, researchers found that MLT may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy by improving survival and ameliorating the side effects of chemotherapy(16). Others found that the administration of melatonin alone or in combination with interleukin-2 in conjunction with chemoradiotherapy and/or supportive care in cancer patients with advanced solid tumors, has been associated with improved outcomes of tumor regression and survival. Moreover, chemotherapy has been shown to be better tolerated in patients treated with melatonin(17).

18. Melatonin and breast cancer prevention
In the reviews the usefulness of this indoleamine for specific aspects of breast cancer management, particularly in reference to melatonin's antiestrogenic and antioxidant properties, found that the clinical utility of melatonin depends on the appropriate identification of its actions. Because of its SERM (selective estrogen receptor modulators) and SEEM (selective estrogen enzyme modulators) properties, and its virtual absence of contraindications, melatonin could be an excellent adjuvant with the drugs currently used for breast cancer prevention (antiestrogens and antiaromatases)(18).

19. Melatonin in Children
In children and neonates, melatonin has been used widely, including for respiratory distress syndrome, bronchopulmonary dysplasia, periventricular leukomalacia (PVL), hypoxia-ischemia encephalopathy and sepsis. In addition, melatonin can be used in childhood sleep and seizure disorders, and in neonates and children receiving surgery, according to the study by Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine(19).

20. Shift work and cancer risk
About 15-20% of the employees in Europe and in the USA are engaged in shift work that involves night work. In the review of disruption in the melatonin synthesis and its effects on shift workers found that in six out of ten studies, a statistically significant association between night shift work and risk of breast cancer has been shown (OR = 2.2; 95% CI: 1.1-4.5 in nurses in Norway with > 30 years of night shift work). The increased cancer risk has been reported in nurses, radio-telephone operators, flight attendants, and women employed in the enterprises, in which 60% of employees work at night. Most of the analyses have been based on the data from the registries, with limited potential for the exposure assessment and confounders adjustment(20).

21. Melatonin and Drug-mediated ototoxicity and tinnitus

In the study to evaluate the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear, suggested that the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage(21).

22. Melatonin in experimental seizures and epilepsy
Although melatonin is approved only for the treatment of jet-lag syndrome and some types of insomnia, clinical data also suggest that it is effective in the adjunctive therapy of osteoporosis, cataract, sepsis, neurodegenerative diseases, hypertension, and even cancer. In humans, melatonin may attenuate seizures, and it is most effective in the treatment of juvenile intractable epilepsy. Its additional benefits include improved physical, emotional, cognitive, and social functions. On the other hand, melatonin has been shown to induce electroencephalographic abnormalities in patients with temporal lobe epilepsy and increase seizure activity in neurologically disabled children. The hormone showed very low toxicity in clinical practice, according to the study by Department of Pathophysiology, Medical University, PL 20-090 Lublin, Jaczewskiego 8, Poland(22).

23. Melatonin and Treatment of Insomnia in elder
In 3-week and 6-month, randomized, double-blind clinical trials in patients with primary insomnia aged ≥55 years, melatonin PR 2 mg 1-2 h before bedtime was associated with significant improvements relative to placebo in many sleep and daytime parameters, including sleep quality and latency, morning alertness and health-related quality of life. Melatonin PR 2 mg was very well tolerated in clinical trials in older patients, with a tolerability profile that was similar to that of placebo. Short- or longer-term treatment with melatonin PR 2 mg was not associated with dependence, tolerance, rebound insomnia or withdrawal symptoms(23).

24. Melatonin treatment in children with ADHD and chronic sleep onset insomnia
In the study to assess long-term melatonin treatment course, effectiveness and safety in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia (CSOI), researchers at the Department of Neurology, Elisabeth Hospital, Tilburg, The Netherlands, found that long-term melatonin treatment was judged to be effective against sleep onset problems in 88% of the cases. Improvement of behaviour and mood was reported in 71% and 61% respectively. We conclude that melatonin remains an effective therapy on the long term for the treatment of CSOI in children with ADHD and has no safety concerns regarding serious adverse events or treatment related co-morbidity. Discontinuation of melatonin treatment usually leads to a relapse of sleep onset insomnia and in resuming melatonin treatment, even after several years of treatment(24).

25. Melatonin treatment in the circadian sleep disorders: delayed sleep phase syndrome (DSPS) and non-24-hour sleep wake disorder
In the study to evaluate the effect of Melatonin treatment in the circadian sleep disorders: delayed sleep phase syndrome (DSPS) and non-24-hour sleep wake disorder, researchers at the School of Biological Sciences, University of Surrey, Guildford, U.K, showed that compared with placebo, melatonin advanced the sleep period in subjects with DSPS. Melatonin also improved a number of sleep parameters in blind subjects suffering from non-24-hour sleep wake disorder(25).

26. Melatonin and sleep problems in children with neurodevelopmental disorders
In a 12 week double masked randomised placebo controlled phase III trial to test for the efficacy of melatonin in treating sleep problems in children with neurodevelopmental disorders, found that children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required(26)

27. Effects of melatonin on ovarian follicles
In the study to evaluate the histomorphometry and expression of Ki-67 and c-kit in ovarian follicles of pinealectomized or melatonin-treated pinealectomized rats, researchers at the São Paulo Federal University (UNIFESP), showed that melatonin exerts a role on the maintenance of a proper follicular function, and is thus important for ovulation and progesterone production(27).

28. Melatonin on angiogenesis and wound healing
In the study to investigate the effects of melatonin hormone on angiogenesis in wound healing on 100 Wistar-Albino rats, with melatonin dissolved in 0.9% NaCl administered to the study group in a dose of 0.4 mg/kg/rat per day (0.25 cc/rat per day), and 0.9% NaCl to the control group in a dose of 0.25 cc/rat per day. Incisions 5 cm in length were made on the back skin of the rats and the wounds were closed with a skin stapler found that melatonin may have a positive effect on both angiogenesis and wound healing(28).

Sources
(8) http://www.ncbi.nlm.nih.gov/pubmed/11115737
(9) http://www.ncbi.nlm.nih.gov/pubmed/11600542
(10) http://www.ncbi.nlm.nih.gov/pubmed/22622709
(11) http://www.ncbi.nlm.nih.gov/pubmed/12622846
(12) http://www.ncbi.nlm.nih.gov/pubmed/16207291
(12a) http://www.ncbi.nlm.nih.gov/pubmed/22074586
(13) http://www.ncbi.nlm.nih.gov/pubmed/22792106
(14) http://www.ncbi.nlm.nih.gov/pubmed/22724080
(15) http://www.ncbi.nlm.nih.gov/pubmed/22511571
(16) http://www.ncbi.nlm.nih.gov/pubmed/22019490
(17) http://www.ncbi.nlm.nih.gov/pubmed/22753734
(18) http://www.ncbi.nlm.nih.gov/pubmed/22500582
(19) http://www.ncbi.nlm.nih.gov/pubmed/22370283
(20) http://www.ncbi.nlm.nih.gov/pubmed/21870422
(21) http://www.ncbi.nlm.nih.gov/pubmed/21673362
(22) http://www.ncbi.nlm.nih.gov/pubmed/21441606
(23) http://www.ncbi.nlm.nih.gov/pubmed/23044640
(24) http://www.ncbi.nlm.nih.gov/pubmed/19486273
(25) http://www.ncbi.nlm.nih.gov/pubmed/10721041
(26) http://www.ncbi.nlm.nih.gov/pubmed/23129488
(27) http://www.ncbi.nlm.nih.gov/pubmed/23102587
(28) http://www.ncbi.nlm.nih.gov/pubmed/14669079

Saturday, October 27, 2012

Hormone Histamine

Histamine, found within granules of basophils and mast cells (>90% of body stores) is a biogenic amine and an organic nitrogen compound that occurs to various degrees in many foods such as cherries to about 0.17-13.46 ng/g, bananas and grapes, rice and cereals, herbs, olive oil, wine, beer, etc.. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity(a). the hormone, as a neurotransmitter is involved in regulating physiological function in the gut and immune response to foreign pathogens.

1. Histamine regulation in glucose and lipid metabolism via histamine receptors
In the study to to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet, showed that severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose(1).

2. Histamine intolerance
According to the study of University of Bonn, Bonn, diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines(2).

3. The role of histamine H1 and H4 receptors in allergic inflammation
Antihistamines are inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists, researchers at the Johnson & Johnson Pharmaceutical Research & Development, L.L.C. San Diego, suggested that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions(3).

4. Oral provocation with liquid histamine
75 mg of pure liquid oral histamine--a dose found in normal meals--can provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance. In a randomized, double-blind, placebo-controlled cross-over study in 10 healthy females (age range 22-36 years, mean 29.1 +/- 5.4) who were hospitalized and challenged on two consecutive days with placebo (peppermint tea) or 75 mg of pure histamine (equaling 124 mg histamine dihydrochloride, dissolved in peppermint tea), researchers found that after histamine challenge, 5 of 10 subjects showed no reaction. One individual experienced tachycardia, mild hypotension after 20 minutes, sneezing, itching of the nose, and rhinorrhea after 60 minutes. Four subjects experienced delayed symptoms like diarrhea (4x), flatulence (3x), headache (3x), pruritus (2x) and ocular symptoms (1x) starting 3 to 24 hours after provocation. No subject reacted to placebo. No changes were observed in histamine and DAO levels within the first 80 minutes in non-reactors as well as reactors. There was no difference in challenge with histamine versus challenge with placebo(4).

5. Atopic Dermatitis with a Low-histamine Diet
In a study to evaluate a six-year-old Korean boy with AD admitted to the hospital for evaluation of the possibility of food, particularly pork, as a triggering factor in his skin disease, found that in an oral food challenge test, he showed a positive result after eating 200 g of pork, but did not show a positive result after eating 60 g of pork. After discharge, we attempted to keep him on a balanced diet that included various types of food and prohibited him from eating food that contains a high level of histamine. After keeping the patient on a balanced and low-histamine dietary regimen, his AD symptoms showed improvement and have not worsened for more than seven months. A low-histamine, balanced diet could be helpful for AD patients having symptoms that resemble histamine intolerance in which their AD symptoms worsened after intake of histamine-rich foods, but in which food allergy tests are negative(5).

6. Histamine H3 receptors and sleep-wake regulation
The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H(3) receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications, according to the study of Integrative Physiology of Brain Arousal Systems, Claude Bernard University(6).

7. Histamine and neuropsychiatric disorders
Brain histamine is involved in a wide range of physiological functions such as regulation of sleep-wake cycle, arousal, appetite control, cognition, learning and memory mainly through the 4 receptor subtypes: H1, H2, H3 and H4, according to the study of Dr. Tashiro M, and Dr. Yanai K. at the Tohoku University Cyclotron and Radioisotope Centre, a series of clinical studies on histamine H1 antagonists, or antihistamines, have demonstrated that antihistamines can be classified into sedative, mildly-sedative and non-sedative drugs according to their blood-brain barrier (BBB) permeability, showing apparent clinical usefulness regarding QOL, work efficiency and traffic safety of allergic patients. PET has also been used for elucidation of aging effects and pathophysiological roles of histaminergic nervous system in various neuropsychiatric disorders such as Alzheimer's disease, schizophrenia and depression, where H1 receptor binding potentials were lower than age-matched healthy controls. It has been also demonstrated that brain histamine functions as an endogenous anti-epileptic. In addition, H3 receptors are located in the presynaptic sites of not only histaminergic nerves but also in other nervous systems such as serotonergic, cholinergic and dopaminergic systems, and to be regulating secretion of various neurotransmitters. Nowadays, H3 receptors have been thought to be a new target of drug treatment of various neuropsychiatric disorders(7).

8. Histamine and men sexual arousal
In the study to evaluate the course of histamine plasma levels through different stages of sexual arousal in the systemic and cavernous blood of healthy male subjects of 34 healthy men, researchers at the Department of Urology & Urological Oncology, Hannover Medical School, showed that histamine slightly decreased in the cavernous blood when the penis became tumescent. During rigidity, histamine decreased further but remained unaltered in the phase of detumescence and after ejaculation. In the systemic circulation, no alterations were observed with the initiation or termination of penile erection, whereas a significant drop was registered following ejaculation. Results are not in favour of the hypothesis of an excitatory role of histamine in the control of penile erection. Nevertheless, the amine might mediate biological events during the post-ejaculatory period(8).

9.The role of histamine on cognition
The specific participation of histamine in cognitive functions followed a slow and unclear pathway because the many different experimental learning models, pharmacologic approaches, systemic and localized applications of the histamine active compounds into the brain used by researchers showed facilitating or inhibitory effects on learning, generating an active issue that has extended up to present time. The specific histamine receptors and the compartmentalizing proprieties of the brain that might explain the apparent inconsistent effects of the imidazolamine in learning. In addition, a hypothetical physiologic role for histamine in memory is proposed under the standard theories of learning in experimental animals and humans.according to the study of Dr. Edgardo O. Alvarez at the Universidad Nacional de Cuyo, Laboratorio de Neuropsicofarmacología Experimenta(9).

10. Histamine and schizophrenia
In a study of a strong hyperactivity of histamine neurons induced in rodent brain by administration of methamphetamine or NMDA-receptor antagonists, Dr. Arrang JM. at the Unité de Neurobiologie et Pharmacologie Moléculaire, found that H3-receptor antagonists/inverse agonists display antipsychotic-like properties in animal models of the disease. Because of the limited predictability value of most animal models and the paucity of drugs affecting histaminergic transmission that were tried so far in human, the evidence remains therefore largely indirect, but supports a role of histamine neurons in schizophrenia(10).

11. Histamine and eating behavior
Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity, researchers at the found that the appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H(1) receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H(1) receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H(3) receptors as a target of antiobesity therapeutics(11)

12. Histamine and the effects on nasal mucous membrane
In the study to examine the reliability of suppression of the histamine wheal and flare reaction in the skin to predict an antihistamine's clinical efficacy in two common allergic diseases seasonal allergic rhinitis and chronic idiopathic urticaria, showed that although histamine is one mediator in the allergic response in the skin and nasal mucosa, many other agents are important modulators of the allergic response. In addition, the major structural and functional differences that exist between the nasal mucosa and the skin affect the type of local response. These manifest themselves as differences between the responses to antigen and histamine challenge in the skin and the nose. The allergic responses in these tissues are not simply the consequence of one chemical but are the result of a cascade of interactions among various cells and mediators. The clinical manifestations of these complex interactions obviously cannot be fully replicated by injection of one chemical mediator, histamine, into the outer layer of the skin. Studies with antihistamines have shown that certain drugs, such as cetirizine, are more suppressive than others (loratadine, terfenadine) in controlling the histamine-induced wheal and flare reaction in the skin. When the clinical efficacy of these medications is compared in clinical trials in seasonal allergic rhinitis and chronic idiopathic urticaria, all are equally efficacious in controlling symptoms(12).

13. Histamine and smooth muscle cells
Acoording to the study by The University of Tennessee, histamine markedly induces protein kinase D (PKD) activation in human aortic smooth muscle cells (HASMCs). PKD belongs to a family of serine/threonine protein kinases, and its function in vascular disease is largely unknown. Histamine-induced PKD phosphorylation is dependent on the activation of histamine receptor 1 (H1) and protein kinase C (PKC). PKD2 predominantly mediates histamine-induced TF expression via the p38 MAPK pathway, while PKD1 mediates histamine-induced TF expression through a p38 MAPK-independent pathway. PKD is a new component in histamine signaling in live cells and that PKD has a novel function in the histamine signaling pathway leading to gene expression, as evidenced by TF expression. Importantly, our data reveal a regulatory link from histamine to PKD and TF, providing new insights into the mechanisms of coagulation and the development of atherothrombosis(13).

14. Histamine and variant angina and acute coronary syndromes
Histamine can induce coronary vasospasm, leading to variant angina and acute myocardial infarction, according to the study by Cardiovascular Research, Physiology Institute, University of Zurich, histamine induces expression of TF, but not TF pathway inhibitor, in vascular cells via activation of the H1, but not H2, receptor. This effect is mediated by the MAP kinases p38, ERK, and JNK. This observation may open novel perspectives in the treatment of variant angina and acute coronary syndromes(14).

15. Histamine and endumetrium
In the study to investigate whether histamine was taken up by perivascular adrenergic nerves and released by periarterial nerve stimulation (PNS) to induce vascular responses, showed that histamine treatment for 20 min induced PNS-induced vasoconstriction followed by vasodilation without affecting CGRP-induced vasodilation. Chlorpheniramine, guanethidine, combination of histamine and desipramine, and endothelium-removal abolished PNS-induced vasodilation in histamine-treated preparations. These results suggest that histamine taken up by and released from adrenergic nerves by PNS causes endothelium-dependent vasodilation in rat mesenteric arteries(15).

16. Histamine H4 receptor and CNS
Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. According to the Immunobiology Program, University of Vermont, H(4)R plays a role in determining the frequency of T regulatory (T(R)) cells in secondary lymphoid tissues, and regulates T(R) cell chemotaxis and suppressor activity. Moreover, the lack of H(4)R leads to an impairment of an anti-inflammatory response due to fewer T(R) cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells(16).

17. Histamine-induced vasodilation and vasoconstriction
In the study to examine the vascular response to histamine in rat perfused mesenteric vascular beds with active tone, suggested that histamine induced endothelium-dependent vasodilation via endothelium histamine H(1) receptors and endothelium-independent vasodilation via smooth muscle histamine H(2) receptors. It is also suggested that the histamine-induced endothelium-independent vasoconstriction and vasodilation are mediated by histamine H(1) receptors and perivascular nerves(17).

18. Histamine on Monocyte Adhesion to Vascular Endothelial Cells
The histamine level is high during allergic attacks, and patients with allergy may have chronic inflammatory conditions at which tumor necrosis factor (TNF)-α is extensively released by macrophages. In the study in vitro static and microfluidic flow assays conducted to investigate the combined influence of histamine and TNF-α on adhesion of monocytic THP-1 cells to human umbilical vein endothelial cells (HUVEC), showed that the number of crawling and firmly adherent THP-1 cells was higher on TNF-α + histamine activated HUVEC than on HUVEC activated by TNF-α alone. This synergistic effect of histamine and TNF-α is caused by the increased endothelial surface expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Since the exposure of TNF-α-activated endothelium to histamine favors monocyte recruitment, it may be a serious risk factor for atherosclerosis and other inflammatory disorders(18).

19. Histamine and IgE-mediated diseases
Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01-0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare)(19).

20. Role of histamine in motion sickness
In the study to elucidate the role of histamine in motion sickness, researchers at the Faculty of Pharmaceutical Sciences, University of Tokyo, found that shaking the animals for 2 min increased HA contents in telencephalon and diencephalon without significantly changing the t-MH levels. alpha-Fluoromethylhistidine (alpha-FMH), which is presumed to deplete the neuronal HA, tended to raise the HA levels. alpha-FMH slightly alleviated the vomiting response to motion stimulus and suppressed the HA increase in diencephalon caused by shaking. Compound 48/80, which releases HA from mast cells, did not alter the control HA levels, but effectively prevented the motion sickness and completely suppressed the motion-induced rises in HA levels. These results provide further evidence that brain HA plays an important role in the development of motion sickness(20).

21. Histamine and motivation
Brain histamine may affect a variety of different behavioral and physiological functions; however, its role in promoting wakefulness has overshadowed its other important functions. Evidence indicated that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors(21).

22. Histamine in addiction and addiction-related behaviors
Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors(22).

23. Low cerebrospinal fluid (CSF) histamine levels and hypersomnia
Researchers at the Akita University School of Medicine confirmed that reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin(23)

24. Histamine and stimulate gastric acid secretion
Ghrelin, a novel growth hormone-releasing peptide, is present in the rat and human stomach and is known to stimulate acid secretion and stomach motility. In the stidy to to elucidate the role of histamine in ghrelin-induced acid secretion in rat stomach. Intravenous administration of ghrelin at 0.8 to 20 microg/kg dose dependently increased gastric acid secretion, as measured by the gastric lumen perfusion method. The maximum response was almost equal to that of gastrin (20 microg/kg), showed that ghrelin increased histidine decarboxylase (HDC) messenger RNA (mRNA) levels, as measured by real-time reverse transcription-polymerase chain reaction using LightCycler. The action of ghrelin on HDC mRNA was abolished by vagotomy. Ghrelin did not affect histamine release from isolated vascularly perfused rat stomach. Taken together, these results suggest that ghrelin stimulates gastric acid secretion via a mechanism involving activation of vagal efferent nerve and histamine release from gastric enterochromaffin-like cells(24).

25. Histamine and neurotransmitter release
In the study to investigate the effect of histamine-3 (H(3)) receptors, expressed in the tuberomammillary nucleus (TMN) of the hypothalamus and in the prefrontal cortex (PFC), on histamine neurotransmission in the rat brain, showed that systemic administration of the selective H(3)-agonist, immepip, decreases, and the reverse H(3) /H(4)-agonist, thioperamide, increases the firing activity of histamine neurons in the TMN and the release of histamine in TMN and PFC. Local perfusion of immepip into the TMN increased, and thioperamide decreased, histamine levels in the TMN but not in the PFC. Local perfusion of immepip into the PFC, however, decreased extracellular histamine levels in both TMN and PFC. It can be concluded that brain H(3) receptors, and especially those expressed in the PFC, play an important role in the autoregulation of histamine neurotransmission(25)

26. Histamine and noradrenaline and acetylcholine
In the study the effects of different histamine concentrations (1 X 10(-6) to 1 X 10(-4)M) on the contractile effects of noradrenaline and acetylcholine on isolated smooth-muscle preparations from rats, showed that histamine increases 2.6 to 16.2 times the noradrenaline concentrations needed for inducing 50 per cent of the maximum contractile response of the anococcygeal muscle. The interaction between noradrenaline and histamine on this smooth-muscle preparation is not competitive. Histamine in the concentrations applied does not influence the contractile effects of noradrenaline on vas deferens and of acetylcholine on tracheal smooth-muscle preparation. In rat anococcygeal muscle histamine most probably influences the contractile effects of noradrenaline and acetylcholine through allosteric interaction with their receptors(26).

27. The role of histamine H4 receptor in immune and inflammatory disorders
In the study the efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples, showed that the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders(27).

28. The role of histamine H1 and H4 receptors in allergic inflammation
In the study to the effect of histamine in allergic inflammatory conditions, showed that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions(28).

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