Browsing by Subject "histamine"

Sort by: Order: Results:

Now showing items 1-9 of 9
  • 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.
  • Koski, Sini K.; Leino, Sakari; Panula, Pertti; Rannanpää, Saara; Salminen, Outi (2020)
    The brain histaminergic and dopaminergic systems closely interact, and some evidence also suggests significant involvement of histamine in Parkinson’s disease (PD), where dopaminergic neurons degenerate. To further investigate histamine-dopamine interactions, particularly in the context of PD, a genetic lack of histamine and a mouse model of PD and levodopa-induced dyskinesia were here combined. Dopaminergic lesions were induced in histidine decarboxylase knockout and wildtype mice by 6-hydroxydopamine injections into the medial forebrain bundle. Post-lesion motor dysfunction was studied by measuring drug-induced rotational behavior and dyskinesia. Striatal tissue from both lesioned and naïve animals was used to investigate dopaminergic, serotonergic and histaminergic biomarkers. Histamine deficiency increased amphetamine-induced rotation but did not affect levodopa-induced dyskinesia. qPCR measurements revealed increased striatal expression of D1 and D2 receptor, DARPP-32, and H3 receptor mRNA, and synaptosomal release experiments in naïve mice indicated increased dopamine release. A lack of histamine thus causes pre- and postsynaptic upregulation of striatal dopaminergic neurotransmission which may be reflected in post-lesion motor behavior. Disturbances or manipulations of the histaminergic system may thus have significant consequences for dopaminergic neurotransmission and motor behavior in both healthy and disease conditions. The findings also represent new evidence for the complex interplay between dopamine and histamine within the nigrostriatal pathway.
  • Chen, Yan; Stegaev, Vasily; Kouri, Vesa-Petteri; Sillat, Tarvo; Chazot, Paul L.; Stark, Holger; Wen, Jian Guo; Konttinen, Yrjo T. (2015)
    To date, conventional and/or novel histamine receptors (HRs) have not been investigated in mouse skeletal myogenesis. Therefore, the present study aimed to investigate the HR-subtypes in skeletal myogenesis. The myogenesis of C2C12 skeletal myoblasts was evaluated using desmin, myogenin and myosin heavy chain (Myh) as early, intermediate and late differentiation markers, respectively. Reverse transcription-quantitative polymerase chain reaction and immunostaining were performed and the messenger RNA (mRNA) expression levels of the HR-subtypes and markers were determined. H1R mRNA was found to be highly expressed in myoblasts at day 0; however, the expression levels were reduced as differentiation progressed. By contrast, H2R mRNA expression remained constant, while H3R mRNA expression increased by 28-, 103- and 198-fold at days 2, 4 and 6 compared with the baseline level (day 0), respectively. In addition, Myh expression increased by 7,718-, 94,487- and 286,288-fold on days 2, 4 and 6 compared with the baseline expression level (day 0). Weak positive staining of the cells for H3R protein was observed on day 2, whereas highly positive staining was observed on days 4 and 6. HR expression during myogenesis was, in part, regulated by the stage of differentiation. These results along with previous findings indicated possible involvement of H1R in the regulation of progenitor cell mitogenesis and of H2R in the relaxation of acetylcholine-stimulated contraction of muscle cells, following the activation of professional histamine-producing cells, including mast cells. By contrast, H3R may participate in the regulation of specialized myocyte functions, potentially by maintaining the relaxed state under the influence of constitutive H3R activity and low histamine concentrations, locally produced/released by non-professional histamine-producing cells.
  • Abdurakhmanova, Shamsiiat; Grotell, Milo; Kauhanen, Jenna; Linden, Anni-Maija; Korpi, Esa R.; Panula, Pertti (2020)
    Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABA(A) receptor delta subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and delta-containing subunit GABA(A) receptors are involved in mediating GABA response.
  • 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.
  • Juhola, Hanna; Postila, Pekka A.; Rissanen, Sami; Lolicato, Fabio; Vattulainen, Ilpo; Rog, Tomasz (2018)
    Lipophilic neurotransmitters (NTs) such as dopamine are chemical messengers enabling neurotransmission by adhering onto the extracellular surface of the post-synaptic membrane in a synapse, followed by binding to their receptors. Previous studies have shown that the strength of the NT-membrane association is dependent on the lipid composition of the membrane. Negatively charged lipids such as phosphatidylserine, phosphatidylglycerol, and phosphatidic acid have been indicated to promote NT-membrane binding, however these anionic lipids reside almost exclusively in the intracellular leaflet of the post-synaptic membrane instead of the extracellular leaflet facing the synaptic cleft. Meanwhile, the extracellular leaflet is relatively rich in biologically relevant anionic gangliosides such as monosialotetrahexosylganglioside (GM1), yet the role of gangliosides in NT-membrane association is not clear. Here, we explored the role of GM1 in modulating the binding of dopamine and histamine (as amphipathicicationic NTs) as well as acetylcholine (as a hydrophilic/cationic NT) with the post-synaptic membrane surface. Atomistic molecular dynamics simulations and free energy calculations indicated that GM1 fosters membrane association of histamine and dopamine. For acetylcholine, this effect was not observed. The in silico results suggest that gangliosides form a charge-based vestibule in front of the post-synaptic membrane, attracting amphipathic NTs to the vicinity of the membrane. The results also stress the importance to understand the significance of the structural details of NTs, as exemplified by the GM1-acetylcholine interaction. In a larger context, the NT-membrane adherence, coupled to lateral diffusion in the membrane plane, is proposed to improve neurotransmission efficiency by advancing NT entry into the membrane-embedded ligand-binding sites. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • 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.
  • Salem, Abdelhakim; Salo, Tuula (2021)
    Oral squamous cell carcinoma (OSCC), the most common oral malignancy, shows an increasing rate of incidence worldwide. In spite of the recent advances in cancer research, OSCC therapy continues to have unfavourable outcomes, and thus patient’s prognosis remains relatively poor. Current research has been devoted to identifying novel therapeutic targets also in the tumour microenvironment (TME). Histamine and its G-protein coupled receptors (H1R-H4R) play vital roles in multiple cancer-associated processes in TME, where histamine is mainly produced by mast cells. However, oral epithelial cells were recently shown to produce low concentrations of histamine in autocrine and paracrine modes. These findings, together with the discovery of the high-affinity histamine H4 receptor, have led to a massive increase in our understanding of histamine functions. This minireview aims to summarize the most recent findings regarding histamine and its receptors and their involvement in oral carcinogenesis—from oral potentially malignant disorders (OPMDs) to invasive OSCC. Importantly, histamine receptors are differentially expressed in OPMDs and OSCC. Furthermore, H1R and H4R are associated with clinicopathological characteristics of OSCC patients, suggesting a role in prognosis. Due to the enormous success of histamine-based medications, histamine receptors may also represent promising and viable drug targets in oral cancer.
  • Chalas, Petros (Helsingin yliopisto, 2020)
    Histamine and hypocretin/orexin are neuromodulators important for regulation of alertness and wakefulness. These systems project to major areas of the brain, are highly conserved among vertebrates and they significantly innervate each other. Different studies have indicated an interaction between the histaminergic and orexin systems, however the role of histamine in this interaction is still not well-established. The goal of this study was to examine possible changes in orexin neurons development and larvae behaviour, after genetic loss of histamine decarboxylase (hdc), the histamine-synthesizing enzyme. Using whole-mount in-situ hybridization and immunofluorescence staining we observed a significant reduction in the expression of the hcrt mRNA and the orexin A peptide in 6 dpf hdcKO zebrafish larvae. However, KO of hdc had no effect on startle response, dark flash response and sleeping behaviour of 6 dpf larvae. To further investigate the regulatory role of the histaminergic system, we employed treatment of hdcWT and KO larvae with ciproxifan, a histamine H3 receptor inverse agonist. Ciproxifan treatment increased darkness habituation in 7 dpf hdcWT and KO larvae but reduced the intensity of the dark flash response only on hdcWT larvae. Furthermore, ciproxifan treatment differentially affected the expression of the orexin A peptide in 7 dpf hdcWT and KO larvae but had no effect on the expression levels of the hcrt mRNA. Collectively, these findings suggest the significance of histaminergic signaling for normal development of orexin neurons and the implication of histamine in the execution of the dark flash response. Lastly, this study indicates the complex role of the histamine H3 receptor and the requirement of further studies for better characterization of its function.