Browsing by Subject "PARKINSONS-DISEASE"

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  • Albert, Katrina; Voutilainen, Merja H.; Domanskyi, Andrii; Airavaara, Mikko (2017)
    Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson's disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson's disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson's disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV--synuclein (-syn) to target substantia nigra dopamine neurons to produce an -syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP), which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in the substantia nigra.
  • Yu, Nancy Y.; Bieder, Andrea; Raman, Amitha; Mileti, Enrichetta; Katayama, Shintaro; Einarsdottir, Elisabet; Fredholm, Bertil B.; Falk, Anna; Tapia-Paez, Isabel; Daub, Carsten O.; Kere, Juha (2017)
    Caffeine is a widely consumed psychoactive substance, but little is known about the effects of caffeine stimulation on global gene expression changes in neurons. Here, we conducted gene expression profiling of human neuroepithelial stem cell-derived neurons, stimulated with normal consumption levels of caffeine (3 mu M and 10 mu M), over a period of 9 h. We found dosage-dependent activation of immediate early genes after 1 h. Neuronal projection development processes were up-regulated and negative regulation of axon extension processes were down-regulated at 3 h. In addition, genes involved in extracellular matrix organization, response for wound healing, and regulation of immune system processes were down-regulated by caffeine at 3 h. This study identified novel genes within the neuronal projection guidance pathways that respond to acute caffeine stimulation and suggests potential mechanisms for the effects of caffeine on neuronal cells.
  • Oksanen, Minna; Lehtonen, Sarka; Jaronen, Merja; Goldsteins, Gundars; Hämäläinen, Riikka H.; Koistinaho, Jari (2019)
    Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood–brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.
  • Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi (2018)
    Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
  • Tietavainen, A.; Gutmann, M. U.; Keski-Vakkuri, E.; Corander, J.; Haeggstrom, E. (2017)
    The control of the human body sway by the central nervous system, muscles, and conscious brain is of interest since body sway carries information about the physiological status of a person. Several models have been proposed to describe body sway in an upright standing position, however, due to the statistical intractability of the more realistic models, no formal parameter inference has previously been conducted and the expressive power of such models for real human subjects remains unknown. Using the latest advances in Bayesian statistical inference for intractable models, we fitted a nonlinear control model to posturographic measurements, and we showed that it can accurately predict the sway characteristics of both simulated and real subjects. Our method provides a full statistical characterization of the uncertainty related to all model parameters as quantified by posterior probability density functions, which is useful for comparisons across subjects and test settings. The ability to infer intractable control models from sensor data opens new possibilities for monitoring and predicting body status in health applications.
  • Bonetti, L; Bruzzone, SEP; Sedghi, NA; Haumann, NT; Paunio, T; Kantojarvi, K; Kliuchko, M; Vuust, P; Brattico, E (2021)
    Predicting events in the ever-changing environment is a fundamental survival function intrinsic to the physiology of sensory systems, whose efficiency varies among the population. Even though it is established that a major source of such variations is genetic heritage, there are no studies tracking down auditory predicting processes to genetic mutations. Thus, we examined the neurophysiological responses to deviant stimuli recorded with magnetoencephalography (MEG) in 108 healthy participants carrying different variants of Val158Met single-nucleotide polymorphism (SNP) within the catechol-O-methyltransferase (COMT) gene, responsible for the majority of catecholamines degradation in the prefrontal cortex. Our results showed significant amplitude enhancement of prediction error responses originating from the inferior frontal gyrus, superior and middle temporal cortices in heterozygous genotype carriers (Val/Met) vs homozygous (Val/Val and Met/Met) carriers. Integrating neurophysiology and genetics, this study shows how the neural mechanisms underlying optimal deviant detection vary according to the gene-determined cathecolamine levels in the brain.
  • Hlushchuk, Irena; Barut, Justyna; Airavaara, Mikko; Luk, Kelvin; Domanskyi, Andrii; Chmielarz, Piotr (2022)
    There are several links between insulin resistance and neurodegenerative disorders such as Parkinson's disease. However, the direct influence of insulin signaling on abnormal alpha-synuclein accumulation-a hallmark of Parkinson's disease-remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological alpha-synuclein accumulation induced by the addition of oc-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect alpha-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor. Subsequently, we tested different media formulations, with and without insulin. Again, removal of insulin from cell culturing media showed no effect on alpha-synuclein accumulation. We observed, however, a reduced alpha-synuclein aggregation in neurons cultured in neurobasal medium with a B27 supplement, regardless of the presence of insulin, in contrast to DMEM/F12 medium with an N2 supplement. The effects of culture conditions were present only in dopaminergic but not in primary cortical or hippocampal cells, indicating the unique sensitivity of the former. Altogether, our data contravene the direct involvement of insulin signaling in the modulation of alpha-synuclein aggregation in dopamine neurons. Moreover, we show that the choice of culturing media can significantly affect preformed fibril-induced oc-synuclein phosphorylation in a primary dopaminergic cell culture.
  • Chalazonitis, Alcmène; Li, ZhiShan; Pham, Tuan D.; Chen, Jason; Rao, Meenakshi; Lindholm, Päivi; Saarma, Mart; Lindahl, Maria; Gershon, Michael D. (2020)
    Abstract Cerebral dopamine neurotrophic factor (CDNF) is expressed in the brain and is neuroprotective. We have previously shown that CDNF is also expressed in the bowel and that its absence leads to degeneration and autophagy in the enteric nervous system (ENS), particularly in the submucosal plexus. We now demonstrate that enteric CDNF immunoreactivity is restricted to neurons (submucosal > myenteric) and is not seen in glia, interstitial cells of Cajal, or smooth muscle. Expression of CDNF, moreover, is essential for the normal development and survival of enteric dopaminergic neurons; thus, expression of the dopaminergic neuronal markers, dopamine, tyrosine hydroxylase, and dopamine transporter are deficient in the ileum of Cdnf -/- mice. The normal age-related decline in proportions of submucosal dopaminergic neurons is exacerbated in Cdnf -/- animals. The defect in Cdnf -/- animals is not dopamine-restricted; proportions of other submucosal neurons (NOS-, GABA-, and CGRP-expressing), are also deficient. The deficits in submucosal neurons are reflected functionally in delayed gastric emptying, slowed colonic motility, and prolonged total gastrointestinal transit. CDNF is expressed selectively in isolated enteric neural crest-derived cells (ENCDC), which also express the dopamine-related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival or these neurons becomes CDNF-dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell-derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long-term maintenance of dopaminergic and other sets of submucosal neurons. This article is protected by copyright. All rights reserved.
  • Lindholm, Päivi; Saarma, Mart (2022)
    Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf(-/-) mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.
  • Albert, Katrina; Raymundo, Diana P.; Panhelainen, Anne; Eesmaa, Ave; Shvachiy, Liana; Araujo, Gabriela R.; Chmielarz, Piotr; Yan, Xu; Singh, Aastha; Cordeiro, Yraima; Palhano, Fernando L.; Foguel, Debora; Luk, Kelvin C.; Domanskyi, Andrii; Voutilainen, Merja H.; Huttunen, Henri J.; Outeiro, Tiago F.; Saarma, Mart; Almeida, Marcius S.; Airavaara, Mikko (2021)
    A molecular hallmark in Parkinson's disease (PD) pathogenesis are a-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of alpha-synuclein. Here, we investigated the effects of CDNF on alpha-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with alpha-synuclein with a KD = 23 +/- 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of alpha-synuclein fibrils and induces the formation of insoluble phosphorylated alpha-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with a-synuclein fibrils, though it did not reduce the number of phosphorylated alpha-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with a-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.
  • Lindahl, Maria; Chalazonitis, Alcmene; Palm, Erik; Pakarinen, Emmi; Danilova, Tatiana; Pham, Tuan D.; Setlik, Wanda; Rao, Meenakshi; Voikar, Vootele; Huotari, Jatta; Kopra, Jaakko; Andressoo, Jaan-Olle; Piepponen, Petteri T.; Airavaara, Mikko; Panhelainen, Anne; Gershon, Michael D.; Saarma, Mart (2020)
    Cerebral dopamine neurotrophic factor (CDNF) is neuroprotective for nigrostriatal dopamine neurons and restores dopaminergic function in animal models of Parkinson's disease (PD). To understand the role of CDNF in mammals, we generated CDNF knockout mice (Cdnf(-/-)), which are viable, fertile, and have a normal life-span. Surprisingly, an age-dependent loss of enteric neurons occurs selectively in the submucosal but not in the myenteric plexus. This neuronal loss is a consequence not of increased apoptosis but of neurodegeneration and autophagy. Quantitatively, the neurodegeneration and autophagy found in the submucosal plexus in duodenum, ileum and colon of the Cdnf(-/-) mouse are much greater than in those of Cdnf(+/+) mice. The selective vulnerability of submucosal neurons to the absence of CDNF is reminiscent of the tendency of pathological abnormalities to occur in the submucosal plexus in biopsies of patients with PD. In contrast, the number of substantia nigra dopamine neurons and dopamine and its metabolite concentrations in the striatum are unaltered in Cdnf(-/-) mice; however, there is an age-dependent deficit in the function of the dopamine system in Cdnf(-/-) male mice analyzed. This is observed as D-amphetamine-induced hyperactivity, aberrant dopamine transporter function, and as increased D-amphetamine-induced dopamine release demonstrating that dopaminergic axon terminal function in the striatum of the Cdnf(-/-) mouse brain is altered. The deficiencies of Cdnf(-/-) mice, therefore, are reminiscent of those seen in early stages of Parkinson's disease.
  • Brodski, Claude; Blaess, Sandra; Partanen, Juha; Prakash, Nilima (2019)
    Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson's Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro.
  • Bazelier, Marloes T.; Eriksson, Irene; de Vries, Frank; Schmidt, Marjanka K.; Raitanen, Jani; Haukka, Jari; Starup-Linde, Jakob; De Bruin, Marie L.; Andersen, Morten (2015)
    PurposeTo identify pharmacoepidemiological multi-database studies and to describe data management and data analysis techniques used for combining data. MethodsSystematic literature searches were conducted in PubMed and Embase complemented by a manual literature search. We included pharmacoepidemiological multi-database studies published from 2007 onwards that combined data for a pre-planned common analysis or quantitative synthesis. Information was retrieved about study characteristics, methods used for individual-level analyses and meta-analyses, data management and motivations for performing the study. ResultsWe found 3083 articles by the systematic searches and an additional 176 by the manual search. After full-text screening of 75 articles, 22 were selected for final inclusion. The number of databases used per study ranged from 2 to 17 (median=4.0). Most studies used a cohort design (82%) instead of a case-control design (18%). Logistic regression was most often used for individual-level analyses (41%), followed by Cox regression (23%) and Poisson regression (14%). As meta-analysis method, a majority of the studies combined individual patient data (73%). Six studies performed an aggregate meta-analysis (27%), while a semi-aggregate approach was applied in three studies (14%). Information on central programming or heterogeneity assessment was missing in approximately half of the publications. Most studies were motivated by improving power (86%). ConclusionsPharmacoepidemiological multi-database studies are a well-powered strategy to address safety issues and have increased in popularity. To be able to correctly interpret the results of these studies, it is important to systematically report on database management and analysis techniques, including central programming and heterogeneity testing. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
  • Suzzi, Stefano; Ahrendt, Reiner; Hans, Stefan; Semenova, Svetlana A.; Chekuru, Avinash; Wirsching, Paul; Kroehne, Volker; Bilican, Saygin; Sayed, Shady; Winkler, Sylke; Spiess, Sandra; Machate, Anja; Kaslin, Jan; Panula, Pertti; Brand, Michael (2021)
    LRRK2 gain-of-function is considered a major cause of Parkinson's disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD. Author summary Parkinson's disease is the second most common degenerative disorder of the brain. Mutations of the LRRK2 gene are the most recurrent genetic cause of pathology, and are thought to result in a more active LRRK2 protein, a large enzyme whose biological function is unclear. Therefore, LRRK2 inhibitors are regarded as promising therapeutics. However, mouse models do not reproduce human pathology unless they also lack LRRK1, and there is evidence of dominant negative effects of LRRK2 mutations. Therefore, the characterization of reliable LRRK2 knockout models might provide insights. In our study, we used the zebrafish as a tractable model to study both early developmental and adult phenotypes resulting from the loss of the entire endogenous lrrk2 gene. We found that mutant embryos displayed subtle brain phenotypes, including reduction of catecholaminergic neurons, the main target of human disease, that spontaneously resolved with development, and a late-onset and progressive increase of dopamine and serotonin degradation consistent with increased MAO enzyme activity. Our results suggest that similar defects might occur in the pre-symptomatic stage of the disease in humans, and warrant further evaluation of LRRK2 inhibition in a therapeutic perspective.
  • Chmielarz, Piotr; Konovalova, Julia; Najam, Syeda Sadia; Alter, Heike; Piepponen, Timo Petteri; Erfle, Holger; Sonntag, Kai C.; Schutz, Gunther; Vinnikov, Ilya A.; Domanskyi, Andrii (2017)
    MicroRNAs (miRs) are important post-transcriptional regulators of gene expression implicated in neuronal development, differentiation, aging and neurodegenerative diseases, including Parkinson's disease (PD). Several miRs have been linked to PD-associated genes, apoptosis and stress response pathways, suggesting that deregulation of miRs may contribute to the development of the neurodegenerative phenotype. Here, we investigate the cell-autonomous role of miR processing RNAse Dicer in the functional maintenance of adult dopamine (DA) neurons. We demonstrate a reduction of Dicer in the ventral midbrain and altered miR expression profiles in laser-microdissected DA neurons of aged mice. Using a mouse line expressing tamoxifen-inducible CreERT2 recombinase under control of the DA transporter promoter, we show that a tissue-specific conditional ablation of Dicer in DA neurons of adult mice led to decreased levels of striatal DA and its metabolites without a reduction in neuronal body numbers in hemizygous mice (Dicer(HET)) and to progressive loss of DA neurons with severe locomotor deficits in nullizygous mice (Dicer(CKO)). Moreover, we show that pharmacological stimulation of miR biosynthesis promoted survival of cultured DA neurons and reduced their vulnerability to thapsigargin-induced endoplasmic reticulum stress. Our data demonstrate that Dicer is crucial for maintenance of adult DA neurons, whereas a stimulation of miR production can promote neuronal survival, which may have direct implications for PD treatment.
  • Jokinen, Viljami; Sidorova, Yulia; Viisanen, Hanna; Suleymanova, Ilida; Tiilikainen, Henna; Li, Zhilin; Lilius, Tuomas O.; Matlik, Kert; Anttila, Jenni E.; Airavaara, Mikko; Tian, Li; Rauhala, Pekka V.; Kalso, Eija A. (2018)
    Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal-and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1-and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid-induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Walkowicz, Lucyna; Kijak, Ewelina; Krzeptowski, Wojciech; Gorska-Andrzejak, Jolanta; Stratoulias, Vassilis; Woznicka, Olga; Chwastek, Elzbieta; Heino, Tapio I.; Pyza, Elzbieta M. (2017)
    In Drosophila melanogaster, mesencephalic astrocyte-derived neurotrophic factor(DmMANF) is an evolutionarily conserved ortholog of mammalian MANF and cerebral dopamine neurotrophic factor (CDNF), which have been shown to promote the survival of dopaminergic neurons in the brain. We observed especially high levels of DmMANF in the visual system of Drosophil a, particularly in the first optic neuropil (lamina). In the lamina, DmMANF was found in glial cells (surface and epithelial glia), photoreceptors and interneurons. Interestingly, silencing of DmMANF in all neurons or specifically in photoreceptors or L2 interneurons had no impact on the structure of the visual system. However, downregulation of DmMANF in glial cells induced degeneration of the lamina. Remarkably, this degeneration in the form of holes and/or tightly packed membranes was observed only in the lamina epithelial glial cells. Those membranes seem to originate from the endoplasmic reticulum, which forms autophagosome membranes. Moreover, capitate projections, the epithelial glia invaginations into photoreceptor terminals that are involved in recycling of the photoreceptor neurotransmitter histamine, were less numerous after DmMANF silencing either in neurons or glial cells. The distribution of the alpha subunit of Na+/K+-ATPase protein in the lamina cell membranes was also changed. At the behavioral level, silencing of DmMANF either in neurons or glial cells affected the daily activity/sleep pattern, and flies showed less activity during the day but higher activity during the night than did controls. In the case of silencing in glia, the lifespan of flies was also shortened. The obtained results showed that DmMANF regulates many functions in the brain, particularly those dependent on glial cells.
  • Di Giorgio, Annabella; Smith, Ryan M.; Fazio, Leonardo; D'Ambrosio, Enrico; Gelao, Barbara; Tomasicchio, Aldo; Selvaggi, Pierluigi; Taurisano, Paolo; Quarto, Tiziana; Masellis, Rita; Rampino, Antonio; Caforio, Grazia; Popolizio, Teresa; Blasi, Giuseppe; Sadee, Wolfgang; Bertolino, Alessandro (2014)
  • Leino, Sakari; Kohtala, Samuel; Rantamäki, Tomi; Koski, Sini K.; Rannanpää, Saara; Salminen, Outi (2018)
    BackgroundThe treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role. Here, female mice with near-total unilateral 6-hydroxydopamine-induced nigrostriatal lesions were chronically treated with levodopa, and the effects of the 7 nicotinic receptor partial agonist AZD0328 and nicotine on LID were assessed. At the end of the experiment, BDNF protein levels in the prefrontal cortex and striatum were measured.ResultsFive-day treatments with three escalating doses of AZD0328 and a 10-week treatment with nicotine failed to alleviate LID. BDNF levels in the lesioned striatum correlated positively with LID severity, but no evidence was found for a levodopa-induced elevation of corticostriatal BDNF in the lesioned hemisphere. The nicotine treatment decreased BDNF levels in the prefrontal cortex but had no effect on striatal BDNF.ConclusionsThe findings suggest that treatment of LID with nicotinic agonists may lose its effectiveness as the disease progresses, represent further evidence for a role for BDNF in LID, and expand previous knowledge on the effects of long-term nicotine treatment on BDNF.
  • Särkamö, Teppo; Altenmueller, Eckart; Rodriguez-Fornells, Antoni; Peretz, Isabelle (2016)