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Srinivasan V.,Sri Sathya Sai Medical Educational and Research Foundation | Cardinali D.P.,Pontifical Catholic University of Argentina | Srinivasan U.S.,MIOT Hospital | Kaur C.,National University of Singapore | And 4 more authors.
Therapeutic Advances in Neurological Disorders | Year: 2011

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. © The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav.


Srinivasan V.,Educational and Research Foundation | Spence D.W.,323 Brock Avenue | Pandi-Perumal S.R.,Somnogen Inc. | Brown G.M.,Center for Addiction and Mental Health | Cardinali D.P.,University of Buenos Aires
International Journal of Alzheimer's Disease | Year: 2011

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. Copyright 2011 Venkatramanujam Srinivasan et al.


Srinivasan V.,Sri Sathya Sai Medical Educational and Research Foundation | Srinivasan V.,Karpagam University | Singh J.,Civil Aviation Authority | Pandi-Perumal S.R.,Somnogen Inc. | And 2 more authors.
Advances in Therapy | Year: 2010

Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT 1 and MT2 melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag. © 2010 Springer Healthcare.


Srinivasan V.,Sri Sathya Sai Medical Educational and Research Foundation | Srinivasan V.,Karpagam University | Pandi-Perumal S.R.,Somnogen Inc | Brzezinsk A.,Hebrew University of Jerusalem | And 3 more authors.
Recent Patents on Endocrine, Metabolic and Immune Drug Discovery | Year: 2011

Melatonin is a natural substance ubiquitous in distribution and present in almost all species ranging from unicellular organisms to humans. In mammals, melatonin is synthesized not only in the pineal gland but also in many other parts of the body, including the eyes, bone marrow, gastrointestinal tract, skin and lymphocytes. Melatonin influences almost every cell and can be traced in membrane, cytoplasmic, mitochondrial and nuclear compartments of the cell. The decline in the production of melatonin with age has been suggested as one of the major contributors to immunosenescence and development of neoplastic diseases. Melatonin is a natural antioxidant with immunoenhancing properties. T-helper cells play an important role for protection against malignancy and melatonin has been shown to enhance T-helper cell response by releasing interleukin-2, interleukin-10 and interferon-γ. 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. In this paper, a brief review of recent patents on melatonin and cancer has also been presented. © 2011 Bentham Science Publishers Ltd.


De Almeida E.A.,São Paulo State University | Di Mascio P.,University of Sao Paulo | Harumi T.,Asahikawa Medical College | Spence D.W.,323 Brock Ave. | And 5 more authors.
Child's Nervous System | Year: 2011

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. © Springer-Verlag 2010.


Bahammam A.,King Saud University | Pandi-Perumal S.,Strategic Technologies Program | Pandi-Perumal S.,Somnogen Inc. | Alzoghaibi M.,King Saud University
Annals of Thoracic Medicine | Year: 2016

Aims: We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. Methods: Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. Results: The participants had a mean age of 26.6 ± 4.9 years and a mean body mass index of 23.7 ± 3.5 kg/m2. No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. Conclusion: In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings. © 2016 Annals of Thoracic Medicine.


Rosenstein R.E.,University of Buenos Aires | Pandi-Perumal S.R.,Somnogen Inc. | Srinivasan V.,Sri Sathya Sai Medical Education and Research Foundation | Spence D.W.,Sleep and Alertness Clinic | And 2 more authors.
Journal of Pineal Research | Year: 2010

Several lines of evidence support the view that increased free radical generation and altered nitric oxide (NO) metabolism play a role in the pathogenesis of highly prevalent ocular diseases, such as glaucoma and uveitis. Data are discussed indicating that melatonin, being an efficient antioxidant that displays antinitridergic properties, has a promising role in the treatment of these ocular dysfunctions. Melatonin synthesis occurs in the eye of most species, and melatonin receptors are localized in different ocular structures. In view of the fact that melatonin lacks significant adverse collateral effects even at high doses, the application of melatonin could potentially protect ocular tissues by effectively scavenging free radicals and excessive amounts of NO generated in the glaucomatous or uveitic eye. © 2010 John Wiley & Sons A/S.


Srinivasan V.,Sri Sathya Sai Medical Educational and Research Foundation | Pandi-Perumal S.R.,Somnogen Inc. | Spence D.W.,Canadian Sleep Institute | Kato H.,Tokyo University of Science | Cardinali D.P.,Pontifical Catholic University of Argentina
Journal of Critical Care | Year: 2010

Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation, immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and regulation of mood. Melatonin has also been reported as effective in combating various bacterial and viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial function and in preventing apoptosis. In a number of animal models of septic shock, as well as in patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the treatment of multiorgan failure are discussed. © 2010 Elsevier Inc.


Bharti V.K.,Indian Veterinary Research Institute | Bharti V.K.,Defence Institute of High Altitude Research DIHAR | Srivastava R.S.,Indian Veterinary Research Institute | Kumar H.,Indian Veterinary Research Institute | And 5 more authors.
Advances in Pharmacological Sciences | Year: 2014

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. © 2014 Vijay K. Bharti et al.


Pandi-Perumal S.R.,Somnogen Inc | Kramer M.,University of Illinois at Chicago
Sleep and Mental Illness | Year: 2010

The diagnosis of mental illness is frequently accompanied by sleep problems; conversely, people experiencing sleep problems may subsequently develop mental illness. Sleep and Mental Illness looks at this close correlation and considers the implications of research findings that have emerged in the last few years. Additionally, it surveys the essential concepts and practical tools required to deal with sleep and co-morbid psychiatric problems. The volume is divided into three main sections: basic science, neuroendocrinology, and clinical science. Included are over 30 chapters on topics such as neuropharmacology, insomnia, depression, dementia, autism, and schizophrenia. Relevant questionnaires for the assessment of sleep disorders, including quality-of-life measurement tools, are provided. There is also a summary table of drugs for treating sleep disorders. This interdisciplinary text will be of interest to clinicians working in psychiatry, behavioral sleep medicine, neurology, pulmonary and critical care medicine. © Cambridge University Press 2010.

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