Department of Neuro- and Psychopharmacology
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by movement disorders (bradykinesia, muscle rigidity, resting tremor) and co-existing non-motor symptoms, including depression. The disease may be accompanied by action tremor. The pathomechanism of this disease is poorly understood, the diagnosis is possible only in the late, irreversible stages, and the available symptomatic therapies are not effective and cause undesirable side effects.
Our research is focused on neurodegeneration of dopamine neurons, the development of compensatory processes, and mechanisms responsible for the major symptoms of PD and essential tremor. Another priority is the search for markers of different stages of PD and potential new drug targets.
We work on animal models involving dopamine (6-OHDA, MPP +, lactacystin, pesticides) and glial (fluorocitrate) cell damage, inhibition of their function (reserpine, tetrabenazine), dopamine receptors blockade (neuroleptics) or action tremor induction (harmaline). The course of degenerative processes and their consequences are analyzed at behavioral (disturbances of motility and coordination, tremor, catalepsy, depressive behavior), histological (immunohistochemistry, stereology), neurotransmitter (microdialysis, HPLC), receptor and transporter (autoradiography), molecular (proteins and mRNA) and metabolic (mitochondrial activity, energy substrates evaluation) levels.
The above models are used to examine the mechanism of action and the effectiveness of potential drugs affecting, among others, dopamine, adenosine, glutamate and nitrergic neurotransmission.
- stereotaxic brain operations in rats and intracerebral administration of compounds
- behavioral methods:
- automatic measurement of locomotor activity, action tremor and other forms of rat motor behavior in actometers
- automatic measurement of asymmetric behavior in rats following unilateral damage of the dopamine system (rotameters)
- observation of rats’ behavior: catalepsy test (a model of akinesia, bradykinesia), measurement of tremulous jaw movements (a model of parkinsonian tremor), cylinder test (motor coordination test), forced swim test (pro and antidepressant behavior model)
- histological methods: histological and immunohistochemical staining of brain sections, light microscopy, stereology
- biochemical methods: HPLC, brain microdialysis, autoradiography of receptors and transporters, measurement of energy substrates concentration in tissues and blood plasma
- molecular methods: Western blot, in situ hybridization, analysis of the mitochondrial respiratory complexes activity
- computer imaging of brain sections, densitometry
The most important discoveries of the last 3 years
We have demonstrated that the dopamine system lesion in rats can model depression associated with Parkinson's disease, and can be used to evaluate the efficacy and side effects of antidepressants as well as their interaction with L-DOPA.
It has been found, that changes in the protein complex composition and performance of the mitochondrial respiratory chain supercomplexes as well as the fluidity of mitochondrial membranes, observed following the dopamine system lesion in rats, might play an important role in the degenerative process and its compensation.
Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence.
Cristina Cadoni, Augusta Pisanu, Nicola Simola, Lucia Frau, Pier Francesca Porceddu, Silvia Corongiu, Christian Dessì, Annesha Sil, Antonio Plumitallo, Jadwiga Wardas, Gaetano Di Chiara
Neuropharmacology, S0028-3908(17)30278-2 10.1016/j.neuropharm.2017.06.008
Depressive-like neurochemical and behavioral markers of Parkinson's disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle.
Kinga Kamińska, Tomasz Lenda, Jolanta Konieczny, Anna Czarnecka, Elżbieta Lorenc-Koci
Pharmacological reports : PR, S1734-1140(17)30231-1 10.1016/j.pharep.2017.05.016
Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.
Adam S Hogendorf, Agata Hogendorf, Rafał Kurczab, Grzegorz Satała, Tomasz Lenda, Maria Walczak, Gniewomir Latacz, Jadwiga Handzlik, Katarzyna Kieć-Kononowicz, Joanna M Wierońska, Monika Woźniak, Paulina Cieślik, Ryszard Bugno, Jakub Staroń, Andrzej J Bojarski
Scientific reports, 10.1038/s41598-017-00822-4
Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA.
Katarzyna Kuter, Łukasz Olech, Urszula Głowacka
Molecular neurobiology, 10.1007/s12035-017-0529-z
Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions.
Grzegorz Satała, Beata Duszyńska, Tomasz Lenda, Gabriel Nowak, Andrzej J Bojarski
Molecular neurobiology, 10.1007/s12035-017-0536-0
Tremorolytic effect of 5'-chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the harmaline-induced model in rats.
Barbara Kosmowska, Krystyna Ossowska, Urszula Głowacka, Jadwiga Wardas
CNS neuroscience & therapeutics, 10.1111/cns.12692
The significance of rotational behavior and sensitivity of striatal dopamine receptors in hemiparkinsonian rats: A comparative study of lactacystin and 6-OHDA.
Jolanta Konieczny, Anna Czarnecka, Tomasz Lenda, Kinga Kamińska, Lucyna Antkiewicz-Michaluk
Neuroscience, S0306-4522(16)30611-X 10.1016/j.neuroscience.2016.10.070
Contribution of the nitric oxide donor molsidomine and the antiparkinsonian drug l-DOPA to the modulation of the blood pressure in unilaterally 6-OHDA-lesioned rats.
Elżbieta Lorenc-Koci, Anna Czarnecka, Kinga Kamińska, Joanna Knutelska, Małgorzata Zygmunt, Magdalena Dudek
Pharmacological reports : PR, S1734-1140(16)30220-1 10.1016/j.pharep.2016.09.022
Antidepressant-like effects of scopolamine in mice are enhanced by the group II mGlu receptor antagonist LY341495.
Karolina Podkowa, Adrian Podkowa, Kinga Sałat, Tomasz Lenda, Andrzej Pilc, Agnieszka Pałucha-Poniewiera
Neuropharmacology, S0028-3908(16)30367-7 10.1016/j.neuropharm.2016.08.031
Native DIGE proteomic analysis of mitochondria from substantia nigra and striatum during neuronal degeneration and its compensation in an animal model of early Parkinson's disease.
Katarzyna Kuter, Manuela Kratochwil, Sven-Hendric Marx, Sonja Hartwig, Stephan Lehr, Michiru D Sugawa, Norbert A Dencher
Archives of physiology and biochemistry,
Early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of lactacystin produces spontaneous contralateral rotations in rats.
J Konieczny, T Lenda, A Czarnecka
Neuroscience, 10.1016/j.neuroscience.2016.02.072 S0306-4522(16)00222-0
The Small GTP-Binding Protein Rhes Influences Nigrostriatal-Dependent Motor Behavior During Aging.
Annalisa Pinna, Francesco Napolitano, Barbara Pelosi, Anna Di Maio, Jadwiga Wardas, Maria Antonietta Casu, Giulia Costa, Sara Migliarini, Paolo Calabresi, Massimo Pasqualetti, Micaela Morelli, Alessandro Usiello
Movement disorders : official journal of the Movement Disorder Society, 10.1002/mds.26489
Adaptation within mitochondrial oxidative phosphorylation supercomplexes and membrane viscosity during degeneration of dopaminergic neurons in an animal model of early Parkinson's disease.
Katarzyna Kuter, Manuela Kratochwil, Klemencja Berghauzen-Maciejewska, Urszula Głowacka, Michiru D Sugawa, Krystyna Ossowska, Norbert A Dencher
Biochimica et biophysica acta, S0925-4439(16)30025-4 10.1016/j.bbadis.2016.01.022
Towards new 5-HT7 antagonists among arylsulfonamide derivatives of (aryloxy)ethyl-alkyl amines: Multiobjective based design, synthesis, and antidepressant and anxiolytic properties.
Vittorio Canale, Rafał Kurczab, Anna Partyka, Grzegorz Satała, Tomasz Lenda, Magdalena Jastrzębska-Więsek, Anna Wesołowska, Andrzej J Bojarski, Paweł Zajdel
European journal of medicinal chemistry, 10.1016/j.ejmech.2015.11.040 S0223-5234(15)30376-7
Adaptive down-regulation of the serotonin transporter in the 6-hydroxydopamine-induced rat model of preclinical stages of Parkinson's disease and after chronic pramipexole treatment.
K Berghauzen-Maciejewska, J Wardas, B Kosmowska, H Domin, M Śmiałowska, U Głowacka, K Ossowska
Neuroscience, S0306-4522(15)01048-9 10.1016/j.neuroscience.2015.11.049
“Control of Motor Function by Adenosine A2A Receptors in Parkinson’s and Huntington’s Disease”
chapter in the book:
Pinna A., Wardas J., Domenici M. R., Popoli P., Cossu G. and Morelli M. “Control of Motor Function by Adenosine A2A Receptors in Parkinson’s and Huntington’s Disease” In: Blum D, Lopes LV, eds., "Adenosine Receptors in Neurodegenerative Diseases", San Diego: Academic Press, 2017: 188-214.
Adenosine A2A receptors: Localization and Function.
Simola N. and WARDAS J.: Adenosine A2A receptors: Localization and Function. (chapter 1)
In: “The Adenosinergic System. A non-dopaminergic target in Parkinson’s disease” Eds. Morelli M, Simola N., Wardas J. Springer International Publishing Switzerland, 2015, pp. 1-25; Current Topics in Neurotoxicity, vol. 10 (Series Eds. Kostrzewa R., Archer T.).
Motor thalamic nuclei as a potential therapeutic target for adenosine in parkinsonian and essential tremor; behavioural, neurochemical and molecular studies in rats, Jadwiga Wardas, PhD
1. Research project objectives/Research hypothesis Essential (ET) and parkinsonian (PD) tremors are relatively frequent neurological disorders in humans. Since mechanisms underlying these tremors are only poorly understood, current pharmacological therapies of these disturbances are highly insufficient. Therefore, there is an urgent need to search for these mechanisms and find out drugs which would be effective at the clinic.The ventral motor thalamus seems to be a brain structure crucial to relay and integrate impulses related to both PD tremor and ET. This region receives glutamatergic inputs from the cerebellum and GABAergic projections from the basal ganglia and therefore seems to be important for convergence of the cerebellar and basal ganglia informations. The present project is devoted to examine whether adenosine and its receptors may be a target for future pharmacotherapy of ET and/or PD tremor. Since adenosine receptors (A1 and A2A) are present in neuronal networks of the ventral thalamic nuclei, the project is focused at examination of a modulatory role of adenosine receptor ligands on ET and PD tremor in animal models and a contribution of the cerebello-thalamic vs basal ganglia-thalamic circuits in these phenomena.
, Katarzyna Kuter, PhD
“MOBILNOSC PLUS” scholarship sponsored by Polish Ministry of Science and Higher Education.
Title: „Protective role of astrocytes in the process of neurodegeneration of dopaminergic cells and during functional compensation of this process. Analysis of function and architecture of mitochondrial oxphos complexes and supercomplexes in animal models of early Morbus Parkinson.”
Performed during three 6 month visits at Technische Universität Darmstadt, Darmstadt, Germany in group of Prof. Norbert A. Dencher.
NCN grant, OPUS 3, Katarzyna Kuter, PhD
OPUS 3 grant nr 2012/05/B/NZ4/02599 financed by National Science Centre (NCN).
Title: „The role of astrocytes and cellular metabolism in functional compensation of degeneration of dopaminergic system in threats brain. Analysis of expression of AMPK and energy sensing proteins in aspect of Parkinson's disease.”
Performed in the Institute of Pharmacology, Polish Academy of Sciences – project leader.
- forced swim test
- HPLC EC
- in situ hybridisation
- in vitro transfection
- locomotor activity
- mass sectroscopy
- microdialysis in vitro
- molecular cloning
- neurochemically specific lesions
- quantitative autoradiography
- radiologand binding
- Real Time PCR
- spectroscopy UV-VIS
- stereotactic implantation of cannulas
- tissue cultures with stable expressing genes encoding selected proteins
- Western Blot
- adenosine receptors
- animal models
- behavioural analysis
- glutamatergic receptors
- metabotropic glutamate receptors
- mitochondrial proteins
- molecular biology
- neurotrophic factors
- nigro-striatal dopaminergic system
- Parkinson's disease