Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 7 uppsatser.

Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal models of AD. Although caloric restriction did not improve mitochondrial function in a transgenic P301L tau model of AD, novel insight into the regulation of F0-F1 ATP synthase activity under CR was gained that may help explain the protective effects of CR in other disease models. In addition, we determined the effects of melatonin treatment on brain mitochondrial cytochrome c oxidase (COX) activity using the transgenic APPSWE mouse model of AD bred to double melatonin receptor (MT1 and MT2) knockout mice. COX activity declined with aging in control mice, but increased with aging in AD mice, most likely as a response to mitochondrial reactive oxygen species (ROS) induced by amyloid-beta generated through APP proteolysis. Both effects were blunted by melatonin treatment. The effects of melatonin were partially dependent on the G-protein coupled melatonin receptors. We also used PD models to identify therapies that restore mitochondrial dysfunction. We showed that overexpression of wild-type alpha synuclein (α-syn) in human neuroblastoma M17 cells resulted in mitochondrial oxygen consumption deficits; similar to the levels observed when PD mutant forms (A30P α-syn, E46K α-syn, and, A53T α-syn) were overexpressed. Mitochondria from cells overexpressing α-syn were more sensitive to a high iron environment, mimicking the physiological conditions in which dopaminergic neurons are found. Diethyl oxaloacetate, succinate, and several amino acids were protective, suggesting the possibility for effective dietary interventions for PD. Lastly, we delineated the level of mitochondrial complex IV activity between gray and white matter in human cervical and lumbar spinal cord, as well as mitochondrial aggregation in the entire neurovascular units (NVU) as a consequence of ALS. At the conclusion of these projects a better understanding of the molecular mechanisms leading to mitochondrial dysfunction in AD, PD, ALS, and aging was gained and promising strategies to delay or reverse these dysfunctions were developed.

Despite teleosts being the largest and most diverse group of vertebrates, fish models currently used to study photoperiodic effects on fish physiology have been limited to a few species, most of which are temperate seasonal breeders. The overall aim of this work was to expand our knowledge on circadian biology and environmental physiological effects in Nile tilapia (Oreochromis niloticus niloticus), a continuous breeding species of tropical-subtropical origin. The circadian light axis of Nile tilapia is described with regards to melatonin production. Circadian melatonin profiles of fish under 12L:12D photoperiods were observed to be low at day and high at night, suggesting melatonin to be an entraining signal as observed in all other vertebrates. When constant light (LL) was used, such day and night fluctuations where abolished. However when fish where exposed to constant darkness (DD) a strong robust endogenous melatonin rhythm was found, suggesting the presence of circadian oscillators in this species. Importantly, this endogenous rhythm was observed to be maintained for at least three weeks under darkness and proved to be circadian in nature. Moreover, although the melatonin system was able to produce day and night melatonin rhythms when exposed to a different (6L:6D) photocycle, the oscillator appeared to not be entrainable to such a short photo cycle when exposed to DD, as melatonin levels remained high. When comparing the circadian organization of different teleost species including Nile tilapia, preliminary studies showed at least three divergent circadian light organizations in teleosts. Nile tilapia was characterised by a pineal gland far less sensitive than in other fish species as demonstrated through in vitro studies. Furthermore, pineal melatonin production was clearly dependent on the light perceived by the eyes as ophthalmectomy resulted in basal plasma melatonin levels during the dark period. These findings are the first to be reported in a teleost and could be comparable to the circadian light organization of higher vertebrates such as mammals. The onset of puberty of Nile tilapia was studied with regards to the newly discovered Kiss1/GPR54 system. Such a system has recently been discovered in mammals and found to be the primary switch of the brain-pituitary-gonadal (BPG) axis. The results of this study not only suggest a link between the Kiss1/GPR54 system and the onset of III puberty in this tropical batch spawning teleost, that would be a highly conserved feature across vertebrates, but also that the transcriptional mechanisms regulating GPR54 expression could be directly or indirectly influenced by light. Finally, a study was conducted on the effects of different intensities of continuous light (LL) on the growth and sexual development of Nile tilapia up to first maturation. The results showed a significant growth response of fish in all LL treatments compared to control fish. Importantly, this confirmed that LL enhances growth in this species and suggests that it is the light regime more than the intensity which is having an effect. This work thus provides important basic knowledge of the light entrainment pathway and circadian melatonin rhythms in Nile tilapia. Of special importance is the discovery of a strong endogenous melatonin oscillator and a novel circadian organization in fish which would seem to be homologous to that observed in higher vertebrates. Moreover, this work provides evidence that the newly discovered Kiss1/GPR54 system has a similar role in fish as has been found in mammals and that such a system could be directly or indirectly regulated by light. If so, Nile tilapia and other fish species could become important models in the chronobiology and reproduction fields. Finally, this work not only increases our basic and applied knowledge of this species, but also broadens our understanding of the circadian light axis in teleosts and its mediatory effects on reproduction.

Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions. The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF). The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin. A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role. In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF. In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks > 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.

Melatonin Therapy for the difficult sleep disorders of children with neurodevelopmental disabilities Dr. James Jan Pediatric Neurologist, Department of Pediatrics, BC Children's Hospital Founder of the Visual Impairment program Sunny Hill Health Centre for Children A Sunny Hill TeleCDR Education Series Presentation Recorded at: Sunny Hill Health Centre for Children on March 15, 2007

Sleep disorders in children provide a frequent cause for parents to seek medical care. If a child has several kinds of sleep disorders and (or) has another illness, their diagnosis and treatment typically become more complicated. Sleep disorders are a frequent comorbidity to epilepsy. In the clinical practice, synthetic melatonin is prescribed for treatment of sleep disorders in children with epilepsy. Clinical trials suggest that melatonin may shorten the duration to sleep onset and balance the sleep structure, leading to decrease in the number of epileptic attacks. However, the melatonin system in these trials has not been explored, and changes of the melatonin system in children with epilepsy are not yet understood. The main objectives of the present study were: i) to determine the most frequent kinds of sleep disorders in children with epilepsy; ii) to characterize the melatonin (MLT) system in children with epilepsy in detail: to describe full diurnal profile, to search correlation with anthropometric data, seizure characteristics (time, type of seizures, antiepileptic medications), as well as the other physiological circadian rhythms (body temperature, pulse, blood pressure). The study results have shown that sleep disorders were more frequent in the group of children with epilepsy (Sleep disorders scale for children (SDSC) (Bruni O et al, 1996)).The most frequent were: the disorders of excessive somnolence (DOES) and sleep - wake transition disorders (SWTD)... [to full text] / Vaikų miego sutrikimai – dažna problema, dėl kurios tėvai kreipiasi į gydytoją. Jei vaikui būdingi keli miego sutrikimai ir (ar) jis serga kita liga, tai diagnozuoti ir gydyti miego sutrikimus yra sudėtinga. Miego sutrikimams ir epilepsijai būdingas komorbidiškumas. Literatūros duomenimis, vaikams, sergantiems epilepsija, empiriškai skiriama sintetinių melatonino preparatų. Įrodyta, kad jie sutrumpina užmigimo laiką, reguliuoja miego struktūrą, todėl retėja epilepsijos priepuoliai. Tačiau epilepsija sergančių vaikų melatonino sistema dar nebuvo tiriama. Darbo tikslas – išsiaiškinti epilepsija sergančių vaikų dažniausius miego sutrikimus ir kankorėžinės liaukos hormono melatonino, jo metabolito 6-sulfatoksimelatonino (aMT6s) paros cirkadinio profilio ypatumus bei ryšį su epilepsijos formomis, priepuoliais, priepuolių laiku, vartojamais vaistais nuo epilepsijos (VNE) bei kitų fiziologinių rodiklių cirkadiniu ritmu (kūno temperatūros, širdies susitraukimų dažnio, arterinio kraujo spaudimo). Rezultatai parodė, kad epilepsija sergančių vaikų miego sutrikimų skalės (VMSS) rodikliai buvo aukštesni visuose miego sutrikimų pogrupiuose. Dažnesni buvo padidėjusio mieguistumo bei miego ir budrumo ritmo sutrikimai. Kontrolinėje ir sergančių epilepsija vaikų grupėse melatonino apykaita, išreikšta ekskrecijos metabolito aMT6s kiekis kūno svorio vienetui, turėjo neigiamą ryšį su amžiumi ir lytinės brandos stadija. Vaikų, sergančių epilepsija, cirkadinis melatonino sekrecijos ir ekskrecijos... [toliau žr. visą tekstą]

Melatonin – is a hormone produced by the pineal gland during the dark time. Light during the night suppresses melatonin production. Melatonin is an important biological body regulator: it controls daily and seasonal biorhythms, glucose metabolism, gonadal activity, cardiovascular system, gastrointestinal tract and the activity of the immune system There is a lot of scientific information about the immunoregulative properties of melatonin. Melatonin modulates the development of some organs of the immune system, cell differentiation, immune response and cytokine production. The imunomodulatory activity of melatonin is usually determined by the following experimental models: surgical pinealectomy, in vivo treatment with melatonin or in vitro treatment of the immune cells with melatonin. However, during the experiments while keeping animals under constant light conditions, melatonin production was rarely naturally inhibited. For the experiments of this study, the method of constant lighting in the mouse model was applied. Our aim was to artificially evoke shift work conditions in order to find out how the deficiency of melatonin production influences the immune system of the shift workers. The results obtained showed that keeping mouse under constant lighting conditions the homeostasis of the immune system (antibody production, leukocyte and granulocyte migration) is disrupted. Therefore, shift work and its influence on the immune system could be considered as a factor for... [to full text] / Melatoninas – tamsiuoju paros metu kankorėžinėje liaukoje gaminamas hormonas. Šviesa nakties metu slopina melatonino produkciją. Melatoninas yra svarbus organizmo biologinis reguliatorius. Jis reguliuoja paros ir sezono bioritmus, gliukozės metabolizmą, lytinių liaukų aktyvumą, širdies ir kraujagyslių sistemos veiklą, virškinimo trakto veiklą, kitų endokrininių liaukų aktyvumą, imuninės sistemos veiklą. Literatūroje paskelbta nemažai duomenų apie imunoreguliacines melatonino savybes. Melatoninas panaikina su amžiumi susijusias užkrūčio liaukos ir blužnies involiucijas, skatina imuninės sistemos ląstelių proliferaciją, pagerina imuninį atsaką. Tyrinėjant imunoreguliacines melatonino savybes daugeliu atvejų taikomi tyrimo metodai, kurių metu atliekamos melatonino injekcijos arba pašalinama pagrindinė melatonino gamybos vieta - kankorėžinė liauka. Tačiau ankstesnių eksperimentų metu melatonino gamyba retai buvo natūraliai slopinama, laikant gyvūnus pastovaus apšvietimo sąlygomis. Disertacijos darbuose buvo taikytas pastovaus apšvietimo metodas modelinėje pelių sistemoje. Taip buvo siekta atkurti pamaininio darbo sąlygas ir ištirti galimą melatonino trūkumo poveikį žmonių, dirbančių pamaininį darbą, imuninei sistemai. Gauti rezultatai rodo, kad, laikant peles pastovaus apšvietimo sąlygomis, sutrinka jų imuninės sistemos homeostazė: antikūnų gamyba, leukocitų, granuliocitų migravimas. Dirbant pamaininį darbą reikėtų atkreipti dėmesį į jo poveikį imuninei sistemai ir įvertinti... [toliau žr. visą tekstą]

Melatoninas – tamsiuoju paros metu kankorėžinėje liaukoje gaminamas hormonas. Šviesa nakties metu slopina melatonino produkciją. Melatoninas yra svarbus organizmo biologinis reguliatorius. Jis reguliuoja paros ir sezono bioritmus, gliukozės metabolizmą, lytinių liaukų aktyvumą, širdies ir kraujagyslių sistemos veiklą, virškinimo trakto veiklą, kitų endokrininių liaukų aktyvumą, imuninės sistemos veiklą. Literatūroje paskelbta nemažai duomenų apie imunoreguliacines melatonino savybes. Melatoninas panaikina su amžiumi susijusias užkrūčio liaukos ir blužnies involiucijas, skatina imuninės sistemos ląstelių proliferaciją, pagerina imuninį atsaką. Tyrinėjant imunoreguliacines melatonino savybes daugeliu atvejų taikomi tyrimo metodai, kurių metu atliekamos melatonino injekcijos arba pašalinama pagrindinė melatonino gamybos vieta - kankorėžinė liauka. Tačiau ankstesnių eksperimentų metu melatonino gamyba retai buvo natūraliai slopinama, laikant gyvūnus pastovaus apšvietimo sąlygomis. Disertacijos darbuose buvo taikytas pastovaus apšvietimo metodas modelinėje pelių sistemoje. Taip buvo siekta atkurti pamaininio darbo sąlygas ir ištirti galimą melatonino trūkumo poveikį žmonių, dirbančių pamaininį darbą, imuninei sistemai. Gauti rezultatai rodo, kad, laikant peles pastovaus apšvietimo sąlygomis, sutrinka jų imuninės sistemos homeostazė: antikūnų gamyba, leukocitų, granuliocitų migravimas. Dirbant pamaininį darbą reikėtų atkreipti dėmesį į jo poveikį imuninei sistemai ir įvertinti... [toliau žr. visą tekstą] / Melatonin – is a hormone produced by the pineal gland during the dark time. Light during the night suppresses melatonin production. Melatonin is an important biological body regulator: it controls daily and seasonal biorhythms, glucose metabolism, gonadal activity, cardiovascular system, gastrointestinal tract and the activity of the immune system There is a lot of scientific information about the immunoregulative properties of melatonin. Melatonin modulates the development of some organs of the immune system, cell differentiation, immune response and cytokine production. The imunomodulatory activity of melatonin is usually determined by the following experimental models: surgical pinealectomy, in vivo treatment with melatonin or in vitro treatment of the immune cells with melatonin. However, during the experiments while keeping animals under constant light conditions, melatonin production was rarely naturally inhibited. For the experiments of this study, the method of constant lighting in the mouse model was applied. Our aim was to artificially evoke shift work conditions in order to find out how the deficiency of melatonin production influences the immune system of the shift workers. The results obtained showed that keeping mouse under constant lighting conditions the homeostasis of the immune system (antibody production, leukocyte and granulocyte migration) is disrupted. Therefore, shift work and its influence on the immune system could be considered as a factor for... [to full text]

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Biyokimya Anabilim Dalı, 2006. / Bibliyografya var.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.