Browsing by Subject "histamiini"

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  • Aaltonen, Linda (Helsingfors universitet, 2015)
    Parkinson's disease is a neurodegenerative disease where the nigrostriatal dopaminergic cells die gradually causing severe motor symptoms. Current treatment of the disease relieves the symptoms but does not affect the progression of the disease, nor does it have a neuroprotective effect. The most important drug for the treatment of Parkinson's disease is L-dopa, the precursor of dopamine. With long-term use, L-dopa loses its efficacy and patients start to get adverse effects. The most significant adverse effects are abnormal involuntary movements called dyskinesias. In the literature review of this thesis Parkinson's disease and its treatment is briefly described. Review focuses on the description of the brain cholinergic and histaminergic systems and their receptors along with the available studies about cholinergic and histaminergic neurotransmission in Parkinson's disease 6-hydroxydopamine (6-OHDA) rodent model. The experimental part of this thesis consisted of two different set of experiments and in both of these the dopamine neurons were destroyed unilaterally by injecting 6-OHDA into the striatum. The aim of the first experiment was to examine histamine H3-receptor antagonist JNJ-39220675 and α7-nicotinic receptor agonist PHA-543613, and their combination therapy effects on motor function and the concentrations of striatal neurotransmitters in hemiparkinsonian mice. Effects on motor function were studied two and four weeks after the 6-OHDA injection with cylinder test, the D-amphetamine-induced rotations, and the inverted grid test. After behavioral tests, mice were sacrificed and striatal neurotransmitter concentrations were determinated by HPLC. The aim of the second experiment was to examine if nicotine can relieve L-dopa-induced dyskinesias. In this experiment 6-OHDA was injected at two sites into the striatum, which was intended to produce more extensive destruction of dopaminergic neurons than in the first experiment. The extent of the lesion by 6-OHDA was verified before starting chronic L-dopa treatments with cylinder test. One month after the 6-OHDA injection, five mice were sacrificed and their striatum and substantia nigra sections were measured for destruction of dopaminergic neurons by immunohistochemical TH-staining. Chronic L-dopa treatment with benserazide was started 49‚àí63 days after the 6-OHDA injection. At the same time, mice were divided into two groups. Half of them got normal drinking water and half got nicotine water. During the chronic L-dopa treatment, development of dyskinesias was observed once a week by video tracking. The cylinder test was also done once again after starting the L-dopa treatment. In the first experiment, H3-receptor antagonist JNJ-39220675 showed promising results in improving motor function. Mice used the impaired (contralateral) paw more in the cylinder test and rotated less to the ipsilateral side in the D-amphetamine-induced rotation test than control animals two weeks after the 6-OHDA injection. Combination therapy also reduced the ipsilateral rotations but in the cylinder test it had no effect two weeks after 6-OHDA injection. Because the asymmetry in behavioural tests were caused by destroying dopaminergic neurons, balancing of the motor skills can result from decreased levels of dopamine in the intact side or from increased dopamine levels or stronger dopaminergic postsynaptic transmission in the lesion side. The results four weeks after 6-OHDA injection are not reliable because the striatal samples showed that dopamine concentrations in the lesion side were very close to that of the intact side indicating recovery from the lesion. In the second experiment, mice developed dyskinesias which were decreased with nicotine treatment. Mice also used the contralateral side paw less indicative of loss of dopamine neurons. In agreement, TH-immunostaining confirmed significant loss of TH-positive neurons. Based on these findings, the 6-OHDA injection site, the selected drug doses, and the experimental design seem to fit the evaluation of dyskinesias. The occurrence of dyskinesias and nicotine's effect on them was seen strongest in the body movements. Dyskinesias in forelimbs were minor, but the nicotine treatment decreased them also.
  • Pihlajasaari, Annika; Leinonen, Elina; Markkula, Annukka; Miettinen, Ilkka (THL); Rimhanen-Finne, Ruska (THL); Summa, Maija; Zacheus, Outi (THL) (Ruokavirasto, 2021)
    Ruokaviraston julkaisuja 7/2021
    Vuosina 2017–2019 Ruokaviraston ylläpitämään elintarvike- ja vesivälitteisten epidemioiden rekisteriin luokiteltiin tehtyjen epidemiaselvitysten perusteella yhteensä 169 elintarvike- tai talousvesivälitteistä epidemiaa, joista 96 % oli elintarvikevälitteisiä. Talousvesivälitteisiä epidemioita raportoitiin samana ajanjaksona 7. Elintarvikkeiden välityksellä ilmoitettiin sairastuneen yhteensä 2 900 henkilöä ja talousveden välityksellä 567 henkilöä. Kuten aikaisemminkin 2000-luvulla, norovirus oli vuosina 2017–2019 yleisin raportoitu elintarvikevälitteisten epidemioiden aiheuttaja. Norovirus aiheutti 57 (35 %) elintarvikevälitteistä epidemiaa. Suurimmat elintarvikevälitteiset epidemiat aiheutti norovirus hoitolaitosruokailun välityksellä vuonna 2018 (292 ja 110 sairastunutta). Yleisimmät raportoidut välittäjäelintarvikkeet olivat kala ja kalavalmisteet sisältäen äyriäiset ja simpukat. Ne aiheuttivat 14 (9 %) epidemiaa. Toiseksi yleisin välittäjä oli liha ja lihavalmisteet sekä kasvikset ja niistä valmistetut tuotteet (kumpikin 12 epidemiaa; 7 %). Yli 70 %:ssa epidemioista välittäjäelintarvike jäi tuntemattomaksi tai välittäjäksi epäiltiin useita ruokia. Saastuneen raaka-aineen käytöllä oli selvä yhteys 33 (20 %) epidemian syntyyn. Raportoiduista epidemioista 22 %:n taustalla oli lämpötilaan ja säilytysaikaan liittyviä puutteita ja virheitä. Infektoituneen keittiötyöntekijän osallistuminen ruoanvalmistukseen ja puutteellinen käsihygienia oli syynä 19 %:iin elintarvikevälitteisistä epidemioista ja näissä melkein kaikissa tapauksissa aiheuttajana oli norovirus. Elintarvikevälitteisten epidemioiden tapahtumapaikaksi raportoitiin useimmiten ravintola, kahvila tai hotelli (90 kpl; 56 %) ja toiseksi yleisimmin koti (12 kpl; 7 %). Norovirukset aiheuttivat suurimman osan (3 kpl) tunnistetuista talousvesiepidemioista. Yhdessä epidemiassa epäiltiin sapovirusta aiheuttajaksi. Suurin talousvesivälitteinen epidemia havaittiin Nousiaisissa vuonna 2018. Sairastuneita raportoitiin 463. Taudinaiheuttajiksi epäiltiin mm. sapoviruksia. Vuosien 2017–2019 aikana taudinaiheuttaja jäi tuntemattomaksi 67 (41 %) elintarvikevälitteisessä ja kolmessa talousvesiepidemiassa. Uimavesivälitteisten epidemioiden raportointi alkoi vuonna 2012. Suomessa raportoitiin vuosina 2017– 2019 neljä uimavesivälitteistä epidemiaa, joissa sairastui noin 200 henkilöä. Kolme epidemioista aiheutui noroviruksen ja yksi kampylobakteerin saastuttamasta uimavedestä tai uimarantaympäristöstä. Ulostevahingon saastuttamalla allasvedellä oli mahdollinen yhteys kylpyläympäristön epidemiaan. Jätevedellä saastunut luonnonvesi aiheutti yhden epidemian. Kahdessa uimarantaympäristöön liittyneessä epidemiassa uimaveden saastumisen syytä ei saatu selville.
  • Kinnunen, Marja (Helsingfors universitet, 2015)
    Histamine is a monoamine structured signal molecule, which takes part in many functions of living organisms. It was first found in brain approximately 70 years ago. Neuronal histamine regulates for example biological rhythms, energy metabolism and thermoregulation. In the 1980's, H3-receptor was recognized in the brain. Neuronal histamine regulates functions of other transmitters for example gamma-aminobutyric acid, glutamate, acetylcholine, noradrenaline and dopamine. Currently, the interactions of histamine and dopamine are not well characterized. Though, it is known that histaminergic fibers innerviate almost every dopaminergic area of the brain. There are also several H3-receptors in the striatum and in the limbic system. These brain areas are important for the rewarding effect of dopamine. The aim of the experimental part of this Master's thesis was to examine the location of histaminergic and dopaminergic nervous systems in mouse brain by using immunohistochemistry. Primary antibodies that were produced in rabbit (anti-histamine (HA)) and in mouse (anti-tyrosine hydroxylase (TH)), and secondary anti-rabbit and anti-mouse anti-bodies, that were produced in goat and conjugated with fluorophores, were used in the study. The samples were imaged with a confocal microscope. The primary aim was to find out, in which addiction related brain areas, histamine and dopamine cells and fibers are located and how they are situated in relation to each other. H3-receptor antagonists have been shown to decrease the consumption and rewarding effect of alcohol in animal models. Therefore, it was examined if non-imidazole structured H3-receptor antagonist also inhibits the rewarding effect of amphetamine, and if it decreases the locomotor activity induced by amphetamine. JNJ-39220675, a neutral antagonist of H3-receptor, and behavioral paradigm of conditioned place preference (CPP) were used in the experiment. CPP was also used to find out if D2-receptor agonist quinpirole cause reward or aversion. The effect of JNJ-39220675 on quinpirole's place preference and change in locomotor activity was also investigated. The interactions of these two pharmacological ligands were also examined in a separate locomotor activity experiment. C57BL/6J mice were used in all experiments. The results show that there are possible synaptic connections of histaminergic and dopaminergic system in substantia nigra, supramammillary nucleus, dorsomedial hypothalamic area and ventral periaqueductal grey area. Also, histaminergic nerve fibers innerviate to the dorsal striatum, which regulates motor functions, and to the ventral striatum, which is a part of the rewarding system of the brain. Hence, it is possible that histamine regulates the actions of dopa-mine in these brain areas. The behavioral experiments showed that JNJ-39220675 inhibits acutely increased locomotor activity caused by amphetamine, and decreases desensitation of decreased locomotor action caused by repeated dose of quinpirole. However, JNJ-39220675 did not have any effect on the rewarding effect of amphetamine, which causes strong sensitization. Also, JNJ-39220675 did not have an effect on quinpirole's aversive action. It remains to be seen, if H3-receptor is a potential target for new medicines in the treatment of different brain diseases and addiction in the future.
  • Peltonen, Anna (Helsingfors universitet, 2018)
    Histamine acts as a neurotransmitter in the central and peripheral nervous system and it has a role in various body functions. Histamine neurons spread widely to most of the central nervous system where histamine has an important role in sleep-wake cycles, regulation of appetite, and motor functions. The effects of histamine are mediated mostly by H1-, H2- and H3-receptors in the central nervous system. The synthesis of histamine and the release of histamine from the presynaptic nerve endings are regulated by H3-receptor via negative feedback. H3-receptors are located also on the presynaptic cell membranes of other neurons where they regulate the release of other neurotransmitters. Several animal experiments have shown that H3-receptor-mediated mechanisms have been observed to have an important role in the regulation of the motor functions together with other neurotransmitter systems especially in the basal ganglia area. The histaminergic system is involved in the patophysiology of diseases such as Parkinson’s disease, Tourette’s syndrome and Huntington’s disease where motor performance is impaired. Functional, physiological and genetical changes in the histaminergic system have been observed in patients with these diseases. There are no clinically used histaminergic compounds for the treatment of these diseases, though recently in animal experiments the histaminergic compounds have proved to be promising. The aim of this Master’s thesis study was to examine the effects of histamine deficiency in the brain on the levodopainduced dyskinesias in histidine decarboxylase knock-out mice (HDC KO) (n=9) and wild-type mice (n=12) in a 6-OHDA mouse model of Parkinson’s disease. The mice were injected with a neurotoxic 6-OHDA solution (3 μg) into the right medial forebrain bundle to cause a unilateral dopaminergic lesion. The success of degeneration of dopaminergic neurons were measured by a rotating rod test and amphetamine-induced (2.5 mg/kg) and apomorphineinduced (0.5 mg/kg) rotameter tests. A daily treatment of levodopa and benserazide (4.5 mg/kg, 1.125 mg/kg) was initiated after the behavioural studies for 10 days. On the last day of the treatment the dyskinesias of the mice were filmed for one minute after 20, 40, 60, 80, 100 and 120 minutes after levodopa dose. After the filming, the mice were killed by decapitation and their middle brains were collected for immunohistochemical studies to measure the extent of the dopaminergic lesion. No statistically significant difference was observed between genotypes in levodopa-induced dyskinesias. In previous studies of our study group more severe levodopa-induced dyskinesias were observed in HDC KO mice when the dopaminergic lesion was caused in the striatum in the 6-OHDA mouse model. The degenerated brain area and thereby the extent of the lesion may have importance in observing the difference between levodopa-induced dyskinesias. In this Master’s thesis study the dopaminergic lesions were equally successful with both genotypes. Therefore differently successful lesions between the genotypes can not be the reason why the difference in genotypes in levodopa-induced dyskinesias was not observed. HDC KO mice were observed to have significantly increased ipsilateral rotational behaviour induced by amphetamine in amphetamine-induced rotametry. Previous studies have shown that HDC KO mice have increased dopamine release and high dopamine metabolite levels which might explain the increased rotational behaviour induced by amphetamine in this study. The observations of earlier studies and this Master’s thesis study verify the relation between histaminergic and dopaminergic systems in motor functions.