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1.  Association of Per3 length polymorphism with bipolar I disorder and schizophrenia 
Background
Sleep–wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India.
Methods
Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers.
Results
An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08–2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (χ2=4.634; P<0.03) than in the control group. No significant association was observed in the allele frequencies of four and five repeat alleles in schizophrenia patients when compared with controls.
Conclusion
The occurrence of the five repeat allele of Per3 may be a risk factor for BD-I onset in this ethnic group.
doi:10.2147/NDT.S73765
PMCID: PMC4267513  PMID: 25525361
circadian rhythms; clock genes; Per3 polymorphism; bipolar disorder; schizophrenia
2.  Effects of Melatonin and Epiphyseal Proteins on Fluoride-Induced Adverse Changes in Antioxidant Status of Heart, Liver, and Kidney of Rats 
Several experimental and clinical reports indicated the oxidative stress-mediated adverse changes in vital organs of human and animal in fluoride (F) toxicity. Therefore, the present study was undertaken to evaluate the therapeutic effect of buffalo (Bubalus bubalis) epiphyseal (pineal) proteins (BEP) and melatonin (MEL) against F-induced oxidative stress in heart, liver, and kidney of experimental adult female rats. To accomplish this experimental objective, twenty-four adult female Wistar rats (123–143 g body weights) were divided into four groups, namely, control, F, F + BEP, and F + MEL and were administered sodium fluoride (NaF, 150 ppm elemental F in drinking water), MEL (10 mg/kg BW, i.p.), and BEP (100 µg/kg BW, i.p.) for 28 days. There were significantly (P < 0.05) high levels of lipid peroxidation and catalase and low levels of reduced glutathione, superoxide dismutase, glutathione reductase, and glutathione peroxidase in cardiac, hepatic, and renal tissues of F-treated rats. Administration of BEP and MEL in F-treated rats, however, significantly (P < 0.05) attenuated these adverse changes in all the target components of antioxidant defense system of cardiac, hepatic, and renal tissues. The present data suggest that F can induce oxidative stress in liver, heart, and kidney of female rats which may be a mechanism in F toxicity and these adverse effects can be ameliorated by buffalo (Bubalus bubalis) epiphyseal proteins and melatonin by upregulation of antioxidant defense system of heart, liver, and kidney of rats.
doi:10.1155/2014/532969
PMCID: PMC3984810  PMID: 24790596
4.  Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection 
Sleep disorders constitute major nonmotor features of Parkinson’s disease (PD) that have a substantial effect on patients’ quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT1 and MT2 receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed.
doi:10.1177/1756285611406166
PMCID: PMC3187674  PMID: 22010042
agomelatine; insomnia; light therapy; melatonin; oxidative stress; Parkinson’s disease; ramelteon; REM sleep behavior disorder; tasimelteon
5.  Cerebral Epiphyseal Proteins and Melatonin Modulate the Hepatic and Renal Antioxidant Defense of Rats 
The cerebral epiphysis (pineal gland) secrets melatonin and number of other proteins and peptides. It was thus hypothesized that antioxidant properties of epiphyseal proteins and melatonin could potentially benefit from exogenous therapies. In view of the therapeutic potential of these proteins, the present experiment was conducted to investigate the effect of buffalo epiphyseal proteins (BEP, at 100 μg/kg BW, i.p.) and melatonin (MEL, at 10 mg/kg BW, i.p) on changes in hepatic and renal antioxidant enzymes of adult female Wistar rats. Buffalo epiphyseal proteins significantly (P < .05) increased hepatic lipid peroxidation (LPO), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), reduced glutathione (GSH), and renal LPO, catalase (CAT), GR, GSH, GPx levels as compared to control animals. Similarly, MEL treatment significantly (P < .05) up-regulated hepatic SOD and GPx activity, whereas CAT, GR, GPx, and GSH levels in renal tissues were increased while SOD and LPO remained unaffected. Buffalo epiphyseal protein treatment produced greater effects on hepatic GPx and renal CAT and GSH levels than did MEL. These findings support the conclusion that buffalo epiphyseal proteins and melatonin activate a number of antioxidant mechanisms in hepatic and renal tissues.
doi:10.4061/2011/142896
PMCID: PMC3106360  PMID: 21660111
6.  Melatonin in Mitochondrial Dysfunction and Related Disorders 
Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.
doi:10.4061/2011/326320
PMCID: PMC3100547  PMID: 21629741
7.  Pharmacotherapy of Insomnia with Ramelteon: Safety, Efficacy and Clinical Applications 
Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon is the first melatonin receptor agonist approved by the Food and Drug Administration (FDA) for the treatment of insomnia characterized by sleep onset difficulties. Ramelteon is both a chronobiotic and a hypnotic that has been shown to promote sleep initiation and maintenance in various preclinical and in clinical trials. The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials. These showed little evidence of next-day residual effects, withdrawal symptoms or rebound insomnia. Other studies indicated that ramelteon lacked abuse potential and had a minimal risk of producing dependence or adverse effects on cognitive or psychomotor performance. A 6-month placebo-controlled international study and a 1-year open-label study in the USA demonstrated that ramelteon was effective and well tolerated. Other potential off-label uses of ramelteon include circadian rhythm sleep disorders such as shift-work and jet lag. At the present time the drug should be cautiously prescribed for short-term treatment only.
doi:10.4137/JCNSD.S1611
PMCID: PMC3663615  PMID: 23861638
circadian rhythms; hypnotic; insomnia; melatonin; ramelteon; sleep
8.  Melatonin and Its Agonist Ramelteon in Alzheimer's Disease: Possible Therapeutic Value 
Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid β-protein (Aβ) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing Aβ-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing Aβ-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT1/MT2 receptors in promoting sleep.
doi:10.4061/2011/741974
PMCID: PMC3004402  PMID: 21197086
9.  Measurement of melatonin in body fluids: Standards, protocols and procedures 
Child's Nervous System  2010;27(6):879-891.
Background and Purpose
The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulfatoxymelatonin (a6MTs) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the body’s endogenous oscillatory pacemaker. The primary objective of this review is to ascertain the clinical benefits and limitations of current methodologies employed for detection and quantification of melatonin in biological fluids and tissues.
Data Identification
A search of the English-language literature (Medline) and a systematic review of published articles were carried out.
Study Selection
Articles that specified both the methodology for quantifying melatonin and indicated the clinical purpose were chosen for inclusion in the review.
Data Extraction
The authors critically evaluated the methodological issues associated with various tools and techniques (e.g. standards, protocols, and procedures).
Results of Data Synthesis
Melatonin measurements are useful for evaluating problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. They have also become an important tool for psychiatric diagnosis, their use being recommended for phase typing in patients suffering from sleep and mood disorders. Additionally, there has been a continuous interest in the use of melatonin as a marker for neoplasms of the pineal region. Melatonin decreases such as found with aging are or post pinealectomy can cause alterations in the sleep/wake cycle. The development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids has increasingly been shown to have direct relevance for clinical decision making.
Conclusions
Due to melatonin’s low concentration, as well as the coexistence of numerous other compounds in the blood, the routine determination of melatonin has been an analytical challenge. The available evidence indicates however that these challenges can be overcome and consequently that evaluation of melatonin's presence and activity can be an accessible and useful tool for clinical diagnosis.
doi:10.1007/s00381-010-1278-8
PMCID: PMC3128751  PMID: 21104186
Melatonin; Circadian rhythms; Radioimmunoassay; Enzyme-linked immunoassay; High-performance liquid chromatography; Mass spectrometry; Capillary electrophoresis
11.  Low-dose dexamethasone challenge in women with atypical major depression: pilot study 
Objective
To examine if atypical depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis.
Method
Eight women with atypical major depression and 11 controls with no history of psychiatric illness, matched on age and body mass index, were challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and 1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol samples were drawn at 8 am and 3 pm on the following day.
Results
After the 0.50-mg dexamethasone challenge, mean suppression of morning cortisol was significantly greater in patients with atypical depression (91.9;, standard deviation [SD] 6.8%) than in the controls (78.3%, SD 10.7%; p < 0.01).
Conclusion
These preliminary data add to the growing body of literature that suggests atypical depression, in contrast to classic melancholia, may be associated with exaggerated negative feedback regulation of the HPA axis.
PMCID: PMC149795  PMID: 11836976
corticotropin-releasing hormone; depression, atypical, dexamethasone; hormones; hydrocortisone; mood disorders; stress

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