Krusek J


Full name : Krusek Jan

First name : Jan

Mail : Institute of Physiology Academy of Sciences of the Czech Republic\; Cellular neurophysiology\; Videnska 1083 Prague 4\; Prague\; 14220

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Country : Czech Republic

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Phone : +420241062551

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References (7)

Title : The pharmacology of tacrine at N-methyl-d-aspartate receptors - Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
Author(s) : Horak M , Holubova K , Nepovimova E , Krusek J , Kaniakova M , Korabecny J , Vyklicky L , Kuca K , Stuchlik A , Ricny J , Vales K , Soukup O
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 75 :54 , 2017
Abstract : The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
ESTHER : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedSearch : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedID: 28089695

Title : Cholinergic properties of new 7-methoxytacrine-donepezil derivatives - Sepsova_2015_Gen.Physiol.Biophys_34_189
Author(s) : Sepsova V , Karasova JZ , Tobin G , Jun D , Korabecny J , Cabelova P , Janska K , Krusek J , Skrenkova K , Kuca K , Soukup O
Ref : Gen Physiol Biophys , 34 :189 , 2015
Abstract : Organophosphorus nerve agents inhibit acetylcholinesterase (AChE) which causes the breakdown of the transmitter acetylcholine (ACh) in the synaptic cleft. Overstimulation of cholinergic receptors (muscarinic and nicotinic) by excessive amounts of ACh causes several health problems and may even cause death. Reversible AChE inhibitors play an important role in prophylaxis against nerve agents. The presented study investigated whether 7-methoxytacrine (7-MEOTA) and 7-MEOTA-donepezil derivatives can act as central and peripheral reversible AChE inhibitors and simultaneously antagonize muscarinic and nicotinic receptors. The possible mechanism of action was studied on cell cultures (patch clamp technique, calcium mobilization assay) and on isolated smooth muscle tissue (contraction study). Furthermore, the kinetics of the compounds were also examined. CNS availability was predicted by determining the passive blood-brain barrier penetration estimated via a modified PAMPA assay. In conclusion, this study provides promising evidence that the new synthesized 7-MEOTA-donepezil derivatives have the desired anticholinergic effect; they can inhibit AChE, and nicotinic and muscarinic receptors in the micromolar range. Furthermore, they seem to penetrate readily into the CNS. However, their real potency and benefit must be verified by in vivo experiments.
ESTHER : Sepsova_2015_Gen.Physiol.Biophys_34_189
PubMedSearch : Sepsova_2015_Gen.Physiol.Biophys_34_189
PubMedID: 25504063

Title : The interaction of quaternary reversible acetylcholinesterase inhibitors with the nicotinic receptor - Sepsova_2014_Physiol.Res_63_771
Author(s) : Sepsova V , Krusek J , Karasova JZ , Zemek F , Musilek K , Kuca K , Soukup O
Ref : Physiol Res , 63 :771 , 2014
Abstract : Acetylcholinesterase inhibitors (AChEIs) are used in the treatment of myasthenia gravis (MG). We investigated the effects of AChEIs on peripheral nicotinic receptors (nAChR), which play a crucial role in the treatment of MG symptoms. The positive modulation of those receptors by AChE inhibitors could have an added value to the anti-AChE activity and might be useful in the therapy of MG. Furthermore, to estimate the potential drawbacks of the compounds, cytotoxicity has been assessed on various cell lines. The whole-cell mode of the patch-clamp method was employed. The experiments were performed on medulloblastoma/rhabdomyosarcoma cell line TE671 expressing human embryonic muscle-like receptor with subunits alpha2betagammadelta. The effect of the compounds on cell viability was measured by standard MTT assay (Sigma Aldrich) on ACHN (renal cell adenocarcinoma), HeLa (immortal cell line derived from a cervical carcinoma), HEPG2 (hepatocellular carcinoma) and BJ (skin fibroblasts) cell lines. No positive modulation by the tested AChE inhibitors was observed. Moreover, the compounds exhibited antagonistic activity on the peripheral nAChR. Standard drugs used in MG treatment were shown to be less potent inhibitors of muscle-type nAChR than the newly synthesized compounds. The new compounds showed very little effect on cell viability, and toxicities were comparable to standards. Newly synthesized AChEIs inhibited peripheral nAChR. Furthermore, the inhibition was higher than that of standards used for the treatment of MG. They could be used for the study of nAChR function, thanks to their high antagonizing potency and fast recovery of receptor activity after their removal. However, since no positive modulation was observed, the new compounds do not seem to be promising candidates for MG treatment, even though their cytotoxic effect was relatively low.
ESTHER : Sepsova_2014_Physiol.Res_63_771
PubMedSearch : Sepsova_2014_Physiol.Res_63_771
PubMedID: 25157661

Title : A Resurrection of 7-MEOTA: A Comparison with Tacrine - Soukup_2013_Curr.Alzheimer.Res_10_893
Author(s) : Soukup O , Jun D , Karasova JZ , Patocka J , Musilek K , Korabecny J , Krusek J , Kaniakova M , Sepsova V , Mandikova J , Trejtnar F , Pohanka M , Drtinova L , Pavlik M , Tobin G , Kuca K
Ref : Curr Alzheimer Res , 10 :893 , 2013
Abstract : Alzheimer s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
ESTHER : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedSearch : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedID: 24093535

Title : Effect of tissue-specific acetylcholinesterase inhibitor C-547 on alpha3beta4 and alphabetaepsilondelta acetylcholine receptors in COS cells - Lindovsky_2012_Eur.J.Pharmacol_688_22
Author(s) : Lindovsky J , Petrov KA , Krusek J , Reznik VS , Nikolsky EE , Vyskocil F
Ref : European Journal of Pharmacology , 688 :22 , 2012
Abstract : The C-547 is the most effective muscle and tissue-specific anticholinesterase among alkylammonium derivatives of 6-methyluracil (ADEMS) acting in nanomolar concentrations on locomotor muscles but not on respiratory muscles, smooth muscles and heart and brain acetylcholine esterases (AChE). When applied systematically it could influence peripheral acetylcholine receptors. The aim of the present study was to investigate the effect of C-547 on rat alpha3beta4 (ganglionic type) and alphabetaepsilondelta (muscle type) nicotinic receptors expressed in COS cells. Currents evoked by rapid application of acetylcholine or nicotine were recorded in whole-cell mode by electrophysiological patch-clamp technique 2-4 days after cell transfection by plasmids coding the alpha3beta4 or alphabetaepsilondelta combination of receptor subunits. In cells sensitive to acetylcholine, the application of C-547 evoked no responses. When acetylcholine was applied during an already running application of C-547, acetylcholine responses were only inhibited at concentrations higher than 10(-7)M. This inhibition is not voltage-dependent, but is accompanied by an increased rate of desensitization. Thus in both types of receptors, effective doses are approximately 100 times higher than those inhibiting AChE in leg muscles and similar to those inhibiting respiratory diaphragm muscles and external intercostal muscles. These observations show that C-547 can be considered for symptomatic treatment of myasthenia gravis and other congenital myasthenic syndromes as an inhibitor of AChE in leg muscles at concentrations much lower than those inhibiting muscle and ganglion types of acetylcholine receptors.
ESTHER : Lindovsky_2012_Eur.J.Pharmacol_688_22
PubMedSearch : Lindovsky_2012_Eur.J.Pharmacol_688_22
PubMedID: 22634638

Title : Oxime reactivators and their in vivo and in vitro effects on nicotinic receptors - Soukup_2011_Physiol.Res_60_679
Author(s) : Soukup O , Krusek J , Kaniakova M , Kumar UK , Oz M , Jun D , Fusek J , Kuca K , Tobin G
Ref : Physiol Res , 60 :679 , 2011
Abstract : Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
ESTHER : Soukup_2011_Physiol.Res_60_679
PubMedSearch : Soukup_2011_Physiol.Res_60_679
PubMedID: 21574759

Title : Allosteric modulation of the nicotinic acetylcholine receptor by physostigmine - Svobodova_2005_Ann.N.Y.Acad.Sci_1048_355
Author(s) : Svobodova L , Krusek J , Hendrych T , Vyskocil F
Ref : Annals of the New York Academy of Sciences , 1048 :355 , 2005
Abstract : The action of physostigmine on mouse muscle nicotinic acetylcholine receptor expressed in the COS-7 cell line was studied by the patch-clamp technique. Physostigmine accelerated, by allosteric modulation, the rate of desensitization of whole cell currents induced by acetylcholine and decreased the maximal amplitude in concentration-dependent manner.
ESTHER : Svobodova_2005_Ann.N.Y.Acad.Sci_1048_355
PubMedSearch : Svobodova_2005_Ann.N.Y.Acad.Sci_1048_355
PubMedID: 16154951