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1

Influence of adenosine A2A receptor stimulation on proenkephalin (PENK) and prodynorphin (PDYN) mRNAs expression in rat brain

100%
Wardas J., Lenda T., Kuter K.
Acta Neurobiologiae Experimentalis
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2005
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tom 65
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nr 3
2

An involvement MAPK/ERK1/2 pathway in mechanism of lactacystin-induced cell damage in primary cortical neurons

88%
Jantas D., Konieczny J., Lenda T., Lason W., Lorenc-Koci E.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
|
nr 3
Proteasome dysfunction is involved in pathomechanism of several neurodegenerative diseases where an accumulation of aberrant proteins occurs (e.g. Parkinson’s disease, Alzheimer’s disease). Lactacystin (LC) has been used for induction of proteasome inhibition-dependent neuronal cell death for several years but mechanism of its toxic action on neurons is still poorly understood. In the present study we showed time- and concentration-dependent toxic action of lactacystin (0.25–50 μM) in mouse cortical neurons. Although, lactacystin induced caspase-3 activation, its toxic action was not attenuated by caspase-3 inhibitor AcDEVD-CHO. We demonstrated that inhibitors of MAPK/ERK1/2 cellular signaling (U0126 and PD98052) were protective against LC-evoked cell death as confi rmed by LDH and MTT reduction assays. Moreover, these data were verifi ed by Western Blot analysis, where we observed the increase in ERK1/2 activity after LC treatment and this effect was inhibited by U0126. The obtained data point to engagement of activation of MAPK/ERK1/2 in toxic action of lactacystin and give a rationale for using agents which inhibit this intracellular pathway in treatment of neurodegenerative diseases connected with proteasome dysfunction. Supported by Polish MNSW Scientifi c Network Fund no 26/E-40/BWSN-0023/2008.
3

Dopamine, serotonin and norepinephrine transporters binding in motor brain structures of 6-OHDA-lesioned rats treated chronically with amitriptyline and L-DOPA

88%
Kaminska K., Wardas J., Konieczny J., Lenda T., Lorenc-Koci E.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Depression frequently accompanied to Parkinson’s disease (PD). AIM(S): The aim of the study was to examine the effects of chronic treatment with amitriptyline(AMI) and L-DOPA on binding to dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in the substantia nigra (SN) and striatum (STR) of the unilaterally 6-OHDA-lesioned rats. METHOD(S): Experiments were performed on Wistar Han rats receiving unilaterally 16 µg/4 µl of 6-OHDA into the medial forebrain bundle (MFB). Two weeks later, rats exhibiting at least 100 contralateral turns/1 h in the apomorphine test were treated with AMI (10 mg/kg) and L-DOPA (12 mg/kg), alone or in combination, once daily for 21 consecutive days. The rats were sacrificed 1h after the last injection, their brains were dissected and frozen. The binding of [3H] GBR 12,935 to DAT, [3H] citalopram to SERT and [3H] nisoxetine to NET was assayed on nigral and striatal tissue sections. RESULTS: Injection of 6-OHDA into MFB caused a decline in [3H] GBR 12,935 binding to DAT in the ipsilateral SN and STR. On the contralateral side comes to up-regulation of DAT expression both in the STR and SN. AMI but not L-DOPA alone, lowered DAT expression in the contralateral STR. In the contralateral SN, DAT expression in drug treated groups was maintained at a control level. In the SN, the unilateral lesion of dopaminergic innervation caused a significant up-regulation of [3H] citalopram binding to SERT on both sides while in the STR only on the contralateral side. In both structures, L-DOPA did not change [3H] citalopram binding to SERT while AMI, alone or in combination, decreased it markedly on both sides. L-DOPA also decreased NET expression in the STR on both sides while AMI, alone or in combination maintained at the control level. CONCLUSIONS: Our data indicates that AMI can modulate the release of L-DOPA derived dopamine from serotonergic terminals on ipsilateral side and serotonin on contralateral one. The obtained data is discussed within the context of motor functions in PD.
4

The effect of chronic treatment with the selected SSRIs and L-DOPA on rotational behavior and monoamine metabolism in the motor and limbic brain structures of 6-ohdalesioned rats

76%
Kaminska K., Lenda T., Konieczny J., Czernecka A., Rogoz Z., Lorenc-Koci E.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: The objective of the present study was to examine rotational behavior and monoamine metabolism in motor (striatum, STR; substantia nigra, SN) and limbic (prefrontal cortex, PFC; hippocampus, HIP) brain structures of unilaterally 6-OHDA-lesioned rats treated chronically with the chosen selective serotonin reuptake inhibitors (SSRIs): fluoxetine or paroxetine alone or jointly with L-DOPA. METHODS: The experiment was performed on male Wistar rats injected unilaterally with 6-OHDA (16 μg/4 μl) into the medial forebrain bundle. Two weeks later, the animals were tested for the rotational behavior induced by apomorphine. Rats exhibiting more than 100 contralateral turns/1 h were administered fluoxetine (5 mg/kg) or paroxetine (5 mg/kg) and L-dopa (12 mg/kg), alone or in combination, once daily for 21 consecutive days. Rotational behavior was recorded after the first and the penultimate doses of the examined drugs. The levels of dopamine (DA), serotonin (5-HT), and their metabolites were determined in the tissue homogenates of motor and limbic brain structures 1h after the last drug injections using HPLC method. RESULTS: Chronic combined administration of fluoxetine+L-DOPA significantly increased while paroxetine+L-DOPA decreased the number of contralateral rotations compared to the group receiving L-DOPA alone. L-DOPA given alone or jointly with SSRIs increased DA levels on both sides of all the examined structures. Fluoxetine intensified L-DOPA effect in the HIP while paroxetine in the SN. Joint administration of fluoxetine+L-DOPA decreased 5-HT level in the ipsilateral SN more distinctly than each of these drugs alone. Paroxetine+L-DOPA evoked similar decreases in tissue 5-HT content in the ipsilateral STR, HIP and PFC. CONCLUSION: The obtained data are discussed in the context of motor and psychiatric disturbances observed in Parkinson’s disease. The study was supported by the Project “Depression-MechanismsTherapy” – POIG.01.01.02-12-004/09-00.
5

NS398 (COX-2 INHIBITOR) potentiates the antidepressant-like effects of MTEP (MGLUR5 ANTAGONIST): Involvement of 5-HT system

76%
Stachowicz K., Sowa-Kucma M., Lenda T., Misztak P., Panczyszyn-Trzewik P., Nowak G., Pilc A.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Compounds acting via metabotropic glutamate (mGlu) receptors, exhibit antidepressant activity. Moreover, development of depressive-like behavior in mice is accompanied by elevated level of prostaglandins. In our earlier study, augmentation of antidepressant-like effects of MTEP by NS398 was presented. AIM(S): The aim of this research was to verify the involvement of serotoninergic(5-HT) system in this interaction. METHOD(S): C57Bl/6J male mice were co-treated with MTEP(1 mg/kg; i.p.) and NS398 (3 mg/kg; i.p.) for 7 or 14 days. 24 h after last injection, hippocampus(Hp) and prefrontal cortex(pFC) were collected. The tissue 5-HT and 5-HIAA levels were measured using P680 HPLC system(Dionex, Sunnyvale, CA, USA). Data presented as the mean ±SEM, using one-way ANOVA(n=7–9, Newman-Keuls test), p<0.05 was considered as statistically significant. RESULTS: 14 days co-administration of MTEP with NS398 resulted in statistical significant increase (by 48%) of 5-HT level in pFC [p<0.0001], comparing to the 5-HT level observed after 7 days of administration. Similar picture (increase by 47%) was observed in pFC in 5‑HIAA level [p<0.01]. Quite different picture of changes was observed in Hp, as 5‑HT level was significantly decreased (by 36%) between 7 and 14 days of co-administration of both MTEP with NS398 [p<0.01]. 5-HT:5-HIAA turnover in pFC and Hp, comparing 7 vs. 14 days of co-treatment MTEP with NS398, showed no significant changes[ns]. CONCLUSIONS: Our findings revealed that, chronic co‑treatment MTEP with NS398 affects 5‑HT level in examined brain structures of mice. Observed effect was without changes in 5-HT:5-HIAA turnover, between 7 and 14 days of administration, in pFC and HP of C57Bl/6J mice. This kind of modulation of 5-HT system maybe interesting in the field of psychopharmacology. Further studies are necessary to determine the precise mechanism of interaction of mentioned pathways. FINANCIAL SUPPORT: Study supported by grant UMO-2014/13/D/NZ7/00292.
6

Toxicity of tetrahydroisoquinolines (TIQs) in the HEK293 cell lines expressing dopamine and organic cation transporters

76%
Lenda T., Schulze G., Rommelspacher H., Bonish H., Bojarski A., Lorenc-Koci E.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
7

Low-basicity agonists of serotonin 5-HT7 receptors

52%
Hogendorf A. S., Hogendorf A., Kurczab R., Satala G., Lenda T., Walczak M., Latacz G., Handzlik J., Kiec-Kononowicz K., Wieronska J., Wozniak M., Cieslik P., Bugno R., Staron J., Bojarski A. J.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
The 5-HT7R is involved in many physiological processes, i.e. the regulation of body temperature, circadian rhythm, learning and memory, as well as pathophysiological processes such as mood disorders, anxiety, schizophrenia and pain. None of the known 5-HT7R agonists qualify as perfect radioligand candidates, mainly due to their poor selectivity, metabolic stability or non-optimal ADME properties. Development of new ligands of 5-HT7R of the unique structure and properties. The compounds were concisely synthesized using van Leusen multi-component protocol and receptor affinity (5‑HT7, 1A, 2A, 6, and D2) was tested in radioligand binding assays. The intrinsic clearance was determined using human liver microsomes, whereas cytotoxicity was measured on HEK-293 and HepG2 cells. The pharmacokinetics of a lead compound was tested on CD-1 mice at 5 mg/kg dose (i.p.). The compound ability to reverse MK-801 induced impairment in novel object recognition test was conducted on Albino Swiss mice. Results: We have developed a series of 5-HT7R ligands, which are one of the very few examples of low-basicity aminergic receptor agonists. Lead compounds exhibited high affinity for the 5‑HT7R as well as high efficacy as agonists, excellent selectivity over related CNS targets, high metabolic stability and low toxicity. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain were found for the lead compound. It was also found active in the NOR test. Because the compounds fulfill all the requirements needed for a PET radioligand a synthetic method which enables the incorporation of 11C isotope was developed. The obtained group of selective, low-basicity 5-HT7R receptor agonists has a great potential to be developed as pharmacological tools, radioligands or drug candidates. FINANCIAL SUPPORT: The study was partially supported by the Polish-Norwegian Research Programme operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009–2014 in the frame of the Project PLATFORMex (Pol-Nor/198887/73/2013), www.platformex.eu.
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