Melatonin has a neuroprotective function, which is mediated via its G-protein-coupled MT1 and MT2 receptors. When activated, various downstream pathways are triggered promoting cell protection and survival. By utilizing this function of melatonin, studies have shown positive effects in animal models of neurodegenerative disorders such as Parkinson’s disease (PD). In our previous studies, a physiological dose of melatonin was shown to have neuroprotective effects in the nigrostriatal pathway, as indicated by preservation of tyrosine hydroxylase (TH) immunoreactivity in a 6-hydroxydopamine (6-OHDA) model of PD. We also have reported that transplantation of MT1 receptor-expressing mouse neural stem cells (C17.2) along with melatonin treatment, preserved TH immunoreactivity in a similar PD model. Moreover, others have reported an increase in striatal melatonin levels in 6-OHDA-induced hemiparkinsonian rats. Based on these implications of a close relationship between the dopaminergic and melatonergic systems, we hypothesize that degeneration of dopaminergic neurons induced by 6-OHDA will affect the melatonergic system in the nigrostriatal pathway. In this study, 6-hydroxydopamine was unilaterally injected in the rat striatum or medial forebrain bundle. An apomorphine rotation test showed significant increases in net contralateral rotations (p<0.01) in lesioned animals as compared to sham. Also, a loss of TH immunoreactivity in the striatum and substantia nigra was seen in striatum lesioned groups, confirming lesion-induced degeneration of dopaminergic neurons in the nigrostriatal pathway. There were no significant differences in MT1 receptor protein expression in the striatum and substantia nigra, between all intrastriatal lesioned groups and the sham group. However, 6-OHDA lesions in the medial forebrain bundle caused a significant increase in MT1 receptor mRNA expression on the lesioned side (right) of the ventral midbrain as compared with the contralateral side. These results suggest that MT1 receptors are upregulated in the ventral midbrain following lesion-induced dopaminergic neurodegeneration, and may be involved in an endogenous neuroprotective mechanism. / Thesis / Master of Science (MSc)

Melatonin is a neuroendocrine hormone most often associated with circadian rhythms, but also has antioxidant and vasodilative properties. Through these properties, exogenous melatonin supplementation has been shown to increase both fetal and postnatal parameters in livestock species, however no research has been performed in swine. This project was split into a prenatal and postnatal study, wherein sows were supplemented from approximately gestational day 38 to 100 before undergoing a terminal hysterectomy for the prenatal portion, and from gestational day 60 to farrowing. Melatonin increased fetal morphometrics in a seasonal dependent manner, where fetuses from melatonin supplemented sows had increased measurements in the Spring replicate. Across the Spring and Fall replicates of the prenatal study, melatonin altered expression of circadian regulatory, metabolic, and myogenic genes within the longissimus dorsi. During the postnatal study, offspring from melatonin supplemented dams had increased body weight and altered circadian regulatory, metabolic, and myogenic gene expression.

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Melatonin is a natural antioxidant that has been investigated for properties as a potential spin trap to identify short-lived free radicals. Computational quantum chemistry studies have been performed for the oxidation of melatonin to N1-acetyl-N2-formyl-5-methoxykynuramine. This research focused on modification of melatonin into derivatives and analyzing the change in total molecular energy from melatonin to its oxidation product, as well as the corresponding derivatives. Each of the molecular geometries were optimized at the DFT/B3LYP/6-31G(d), DFT/B3LYP/cc-pVXZ (X = D, T), HF/6-31G(d), HF/cc-PVXZ (X = D, T), MP2/6-31G(d), and MP2/cc-PVXZ (X = D, T) levels of theory. Single point energies were extrapolated to the complete basis set. The results demonstrated that some electron-withdrawing groups increased the total energy of the system. The electron-withdrawing functional group which lowered the total energy of the system was a peroxyl functional group, and this is believed to be due to overlapping constructive interference between molecular orbitals.

Breast cancer is the second most common cancer in women worldwide and the second leading cause of all-cancer mortality. Breast cancer is a multifactorial disease with several elements that contribute to its development. Several lines of evidence suggest that disruptions in circadian rhythm may increase the risk of breast cancer, primarily through decreasing the body’s production of melatonin, a molecule that combats tumorigenesis through antioxidant, anti-angiogenic, and anti-aromatase properties. Sleep characteristics like insomnia, sleep duration, chronotype, and participating in night shift work have all been studied to determine their impact on breast cancer risk. While there is research both in support of and against each of the previously mentioned sleep characteristics’ role in breast cancer development, the majority of studies that have been carried out are supportive of some form of causal association between sleep disturbances and breast cancer incidence and progression. The variability in various studies suggests that sleep disturbance may need to be particularly severe or persist for many years in order to have tumorigenic effects. This connection between sleep and breast cancer suggests that maintaining healthy sleep habits may reduce the risk of breast cancer over time. Taking melatonin supplements, participating in cognitive behavioral therapy, exercising regularly, and limiting exposure to blue light have all been shown to be useful practices for improving sleep quality; thus, these techniques may be useful for reducing breast cancer risk in women who experience sleep disturbances.

Syfte: Syftet med den här litteraturstudien är att undersöka om det finns anledning att bära blåljusblockerande glasögon innan sänggående i syfte att förbättra sömnkvalitet relaterat till ljus, melatonin och skärmarbete kvällstid.   Metod: Det här arbetet är en litteraturstudie som baseras på vetenskapliga publikationer inom området optometri. Publikationerna som valdes hittas via sökning i databasen PubMed och Medline.  Resultat: Av fem artiklar kunde alla visa diverse parametrar med indikation på förbättrad sömn, vilket inkluderade färre uppvaknande och kortare tid att somna, en visade på högre andel djupsömn med blåljusblockerande glasögon jämfört med utan, däremot noterades inga andra positiva mätvärden. Slutligen ökade melatoninhalten signifikant och en ökad total sömn i den sista studien. Studieuppläggen skiljde sig åt i de olika vetenskapliga artiklarna. Slutsats: Sammanfattningsvis visar resultatet av studierna att effekten av blåljusblockerande filter på kvällen är inkonsekventa och det kan inte med säkerhet konstateras att det hjälper sömnkvaliteten, även om mindre förbättringar kan ses. Däremot finns det tydligare evidens för en ökad melatoninhalt vilket kan ha en positiv innebörd för sömnen. Framtida studier behöver inkludera fler deltagare, längre studier och fler objektiva parametrar.

The circadian rhythms are not solely regulated by photoperiod but are also influenced by feed regimen. Therefore, maternal nutrient restriction during gestation could potentially impact the fetal circadian rhythm. Melatonin, a circadian rhythm modulator hormone, has shown to act as an antioxidant reducing reactive oxygen species during stress exposure; and two potential mechanisms have been proposed for melatonin causing vasoconstriction and vasodilation regulating blood flow. In livestock species, nutrient restriction during gestation reduces uterine blood flow, limiting nutrients availability to the fetus for growth and development. Therefore, this project aimed to use beef heifers to evaluate the maternal nutrient restriction and/ or melatonin supplementation in (1) temporal transcript abundance of clock genes, angiogenic factors and nutrient sensing genes in bovine placenta, (2) temporal alterations of uteroplacental blood flow, vaginal temperatures, and placentome vascularization, and (3) fetal morphometrics. Early maternal nutrient restriction did not alter placental explants gene expression. Furthermore, the maternal portion of the placentome exhibited limit temporal variation, while the fetal tissue exhibited a clear temporal rhythm in the mRNA relative abundance of the genes measured. Additionally, melatonin supplementation during late gestation, showed to increased uterine blood flow, reduced vaginal temperatures, and rescued fetal weights during compromised pregnancies in a season dependent manner. In conclusion, the bovine placenta exhibited an autonomous circadian rhythm, while the fetal and maternal circadian rhythms appeared to be independent systems. Future research should examine the effects of melatonin supplementation in fetal organ development.

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<p>Valproic acid (VPA) is clinically utilized as an anti-convulsant and mood stabilizer, though its mechanism of action has not been fully elucidated.<strong> </strong>Evidence suggests an interaction between VPA and the melatonergic system as VPA up-regulated the melatonin MT₁ receptor subtype in rat C6 glioma cells. To determine if the observed effects can translate to an <em>in vivo </em>model, we investigated the effects of chronic VPA administration in a rat model on the expression of MT₁ and MT₂ receptors in the hippocampus. We also investigated the effect of chronic VPA treatment on the expression of the neurotrophic factors BDNF and GDNF in the rat hippocampus and striatum.</p> <p>(1) Animals were separated into two groups with the experimental group receiving VPA (4 mg/mL) for 17 days, and the control receiving vehicle. The hippocampus was dissected and MT₁, MT₂, BDNF and GDNF mRNA were analyzed with RT-PCR. (2) Animals were separated into three groups with the first group receiving VPA (4 mg/mL), the second receiving VPA (3 mg/mL) for 16 days, and the control receiving vehicle. MT₂ mRNA in the hippocampal subregions were analyzed with in situ hybridization.</p> <p>VPA induced the expression of MT₁ and MT₂ mRNA in the hippocampus in the experimental group compared to the control group. VPA also increased MT₂ mRNA expression in the subregions of the hippocampus. Additionally, BDNF and GDNF mRNA expression were increased in the VPA treatment group.</p> <p>These findings raise the interesting question of whether the diverse clinical effects of VPA involve an interaction with the melatonergic system.</p> / Master of Science (MSc)