@article{MTMT:3251043, title = {Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo}, url = {https://m2.mtmt.hu/api/publication/3251043}, author = {Szabó, Zsolt and Héja, László and Szalay, Gergely and Kékesi, Orsolya Sára and Füredi, András and Szebényi, Kornélia and Dobolyi, Árpád and Orbán, Tamás I. and Kolacsek, Orsolya and Tompa, Tamás and Miskolczy, Zsombor and Biczók, László and Rózsa J., Balázs and Sarkadi, Balázs and Kardos, Julianna}, doi = {10.1038/s41598-017-06073-7}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {7}, unique-id = {3251043}, issn = {2045-2322}, abstract = {Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activity in vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activity in vivo coupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca2+ transients reduces the ratio of both astrocytes and neurons involved in SWA. These in vivo findings conclusively suggest a causal role of the astrocytic syncytium in SWA generation.}, keywords = {HUMAN BRAIN; CEREBRAL-CORTEX; sleep; tonic inhibition; NETWORK MECHANISMS; LESS-THAN-1 HZ; GABA RELEASE; Calcium dynamics; GAP-JUNCTION; interneurons}, year = {2017}, eissn = {2045-2322}, orcid-numbers = {Szabó, Zsolt/0000-0002-2902-743X; Füredi, András/0000-0002-7883-9901; Szebényi, Kornélia/0000-0003-1558-8372; Dobolyi, Árpád/0000-0003-0397-2991; Orbán, Tamás I./0000-0002-3424-3428; Biczók, László/0000-0003-2568-5942; Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:2988827, title = {Straightforward and effective synthesis of gamma-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes}, url = {https://m2.mtmt.hu/api/publication/2988827}, author = {Ma, X and Lubin, H and Ioja, Enikő and Kékesi, Orsolya Sára and Simon, Ágnes and Apáti, Ágota and Orbán, Tamás I. and Héja, László and Kardos, Julianna and Marko, IE}, doi = {10.1016/j.bmcl.2015.11.100}, journal-iso = {BIOORG MED CHEM LETT}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, volume = {26}, unique-id = {2988827}, issn = {0960-894X}, abstract = {Supply of major metabolites such as gamma-aminobutyric acid (GABA), beta-alanine and taurine is an essential instrument that shapes signalling, proper cell functioning and survival in the brain and peripheral organs. This background motivates the synthesis of novel classes of compounds regulating their selective transport through various fluid-organ barriers via the low-affinity gamma-aminobutyric acid (GABA) transporter subtype 2 (GAT2). Natural and synthetic spirocyclic compounds or therapeutics with a range of structures and biological activity are increasingly recognised in this regard. Based on pre-validated GABA transport activity, straightforward and efficient synthesis method was developed to provide an azaspiro[4.5]decane scaffold, holding a variety of charge, substituent and 3D constrain of spirocyclic amine. Investigation of the azaspiro[4.5]decane scaffold in cell lines expressing the four GABA transporter subtypes led to the discovery of a subclass of a GAT2-selective compounds with acyl-substituted azaspiro[4.5]decane core.}, year = {2016}, eissn = {1464-3405}, pages = {417-423}, orcid-numbers = {Orbán, Tamás I./0000-0002-3424-3428} } @article{MTMT:2972588, title = {Recurrent seizure-like events are associated with coupled astroglial synchronization.}, url = {https://m2.mtmt.hu/api/publication/2972588}, author = {Kékesi, Orsolya Sára and Ioja, Enikő and Szabó, Zsolt and Kardos, Julianna and Héja, László}, doi = {10.3389/fncel.2015.00215}, journal-iso = {FRONT CELL NEUROSCI}, journal = {FRONTIERS IN CELLULAR NEUROSCIENCE}, volume = {9}, unique-id = {2972588}, issn = {1662-5102}, abstract = {Increasing evidence suggest that astrocytes significantly modulate neuronal function at the level of the tripartite synapse both in physiological and pathophysiological conditions. The global control of the astrocytic syncytium over neuronal networks, however, is still less recognized. Here we examined astrocytic signaling during epileptiform activity which is generally attributed to large-scale neuronal synchronization. We show that seizure-like events in the low-[Mg(2+)] in vitro epilepsy model initiate massive, long-range astrocytic synchronization which is spatiotemporally coupled to the synchronized neuronal activity reaching its maximum at the electrographic tonic/clonic transition. Cross-correlation analysis of neuronal and astrocytic Ca(2+) signaling demonstrates that high degree of synchronization arises not only among astrocytes, but also between neuronal and astrocyte populations, manifesting in astrocytic seizure-like events. We further show that astrocytic gap junction proteins contribute to astrocytic synchronization since their inhibition by carbenoxolone (CBX) or Cx43 antibody increased the interictal interval and in 41% of slices completely prevented recurrent seizure-like activity. In addition, CBX also induced unsynchronized Ca(2+) transients associated with decreasing incidence of epileptiform discharges afterwards. We propose therefore that local, unsynchronized astrocytic Ca(2+) transients inhibit, while long-range, synchronized Ca(2+) signaling contributes to the propagation of recurrent seizure-like events.}, year = {2015}, eissn = {1662-5102}, orcid-numbers = {Szabó, Zsolt/0000-0002-2902-743X} } @article{MTMT:2760570, title = {Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes. nincs}, url = {https://m2.mtmt.hu/api/publication/2760570}, author = {Szabó, Mónika and Veres, Zsuzsa and Bátai-Konczos, Attila and Kékesi, Orsolya Sára and Kis, Emese and Szabó, K and Jemnitz, Katalin}, doi = {10.1016/j.tiv.2014.05.016}, journal-iso = {TOXICOL IN VITRO}, journal = {TOXICOLOGY IN VITRO}, volume = {28}, unique-id = {2760570}, issn = {0887-2333}, year = {2014}, eissn = {1879-3177}, pages = {1136-1143} } @article{MTMT:2540335, title = {GLIAL GABA TRANSPORTERS DOWNREGULATE ENHANCED NEURONAL ACTIVITY}, url = {https://m2.mtmt.hu/api/publication/2540335}, author = {Kékesi, Orsolya Sára and Nyitrai, Gabriella and Szabó, Pál Tamás and Fiáth, Richárd and Ulbert, István and Kardos, Julianna and Héja, László}, journal-iso = {GLIA}, journal = {GLIA}, volume = {61}, unique-id = {2540335}, issn = {0894-1491}, year = {2013}, eissn = {1098-1136}, pages = {S122-S123}, orcid-numbers = {Szabó, Pál Tamás/0000-0003-2260-4641; Fiáth, Richárd/0000-0001-8732-2691; Ulbert, István/0000-0001-9941-9159} } @article{MTMT:2486869, title = {Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists}, url = {https://m2.mtmt.hu/api/publication/2486869}, author = {Muranyi, M and Cinar, Resat and Kékesi, Orsolya Sára and Birkás, Erika and Fábián, Gabriella and Bozó, Bea and Zentai, A and Tóth, Géza and Kicsi, EG and Macsai, M and Dochnal, Roberta and Szabó, Gyula and Szűcs, Mária}, doi = {10.1155/2013/501086}, journal-iso = {BIOMED RES INT}, journal = {BIOMED RESEARCH INTERNATIONAL}, volume = {2013}, unique-id = {2486869}, issn = {2314-6133}, abstract = {Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity".}, keywords = {IN-VIVO; RAT-BRAIN; DESENSITIZATION; TOLERANCE; MORPHINE; internalization; BIASED AGONISM; FUNCTIONAL SELECTIVITY; BETA-ARRESTIN; G-protein activation}, year = {2013}, eissn = {2314-6141}, orcid-numbers = {Fábián, Gabriella/0000-0002-2323-4948; Szabó, Gyula/0000-0002-3409-5357} } @article{MTMT:2429176, title = {Lack of Regulatory Changes of mu-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity.}, url = {https://m2.mtmt.hu/api/publication/2429176}, author = {Cinar, Resat and Kékesi, Orsolya Sára and Birkás, Erika and Fábián, Gabriella and Schmidhammer, H and Szűcs, Mária}, doi = {10.2174/138161281942140105161245}, journal-iso = {CURR PHARM DESIGN}, journal = {CURRENT PHARMACEUTICAL DESIGN}, volume = {19}, unique-id = {2429176}, issn = {1381-6128}, abstract = {Here we have studied regulatory changes of mu-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting mu-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of mu-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous mu-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of mu-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that mu-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist-directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence.}, year = {2013}, eissn = {1873-4286}, pages = {7348-7354}, orcid-numbers = {Fábián, Gabriella/0000-0002-2323-4948} } @article{MTMT:2060849, title = {Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions}, url = {https://m2.mtmt.hu/api/publication/2060849}, author = {Nyitrai, Gabriella and Kékesi, Orsolya Sára and Pál, Ildikó and Keglevich, Péter and Csíki, Zsuzsanna and Fügedi, Péter and Simon, Ágnes and Fitos, Ilona and Németh, Krisztina and Benéné Visy, Júlia and Tárkányi, Gábor and Kardos, Julianna}, doi = {10.3109/17435390.2011.591511}, journal-iso = {NANOTOXICOLOGY}, journal = {NANOTOXICOLOGY}, volume = {6}, unique-id = {2060849}, issn = {1743-5390}, keywords = {Brain; CELLS; DELIVERY; GROWTH; CYTOTOXICITY; NANOPARTICLES; Phosphate; internalization; MOLECULAR SIMULATION; CARRIERS; PAMAM dendrimers; imaging cell death; beta-D-glucopyranose-conjugation; polycationic and polyanionic PAMAM dendrimers; Functional neurotoxicity indicators}, year = {2012}, eissn = {1743-5404}, pages = {576-586}, orcid-numbers = {Pál, Ildikó/0000-0003-2124-9967} } @article{MTMT:1942337, title = {Astrocytes convert network excitation to tonic inhibition of neurons}, url = {https://m2.mtmt.hu/api/publication/1942337}, author = {Héja, László and Nyitrai, Gabriella and Kékesi, Orsolya Sára and Dobolyi, Árpád and Szabó, Pál Tamás and Fiáth, Richárd and Ulbert, István and Pál-Szenthe, Borbála and Palkovits, Miklós and Kardos, Julianna}, doi = {10.1186/1741-7007-10-26}, journal-iso = {BMC BIOL}, journal = {BMC BIOLOGY}, volume = {10}, unique-id = {1942337}, issn = {1741-7007}, year = {2012}, eissn = {1741-7007}, orcid-numbers = {Dobolyi, Árpád/0000-0003-0397-2991; Szabó, Pál Tamás/0000-0003-2260-4641; Fiáth, Richárd/0000-0001-8732-2691; Ulbert, István/0000-0001-9941-9159; Palkovits, Miklós/0000-0003-0578-0387} } @inproceedings{MTMT:1866287, title = {Interactions of polyamidoamine dendrimers with the plasmamembrane of neuronal cells}, url = {https://m2.mtmt.hu/api/publication/1866287}, author = {Pál, Ildikó and Nyitrai, Gabriella and Kékesi, Orsolya Sára and Simon, Ágnes and Kardos, Julianna}, booktitle = {4th European Conference on Chemistry for Life Sciences 4 ECCLS}, unique-id = {1866287}, year = {2011}, pages = {75-78}, orcid-numbers = {Pál, Ildikó/0000-0003-2124-9967} }