A water-soluble polymer cancerostatic actively targeted against cancer cells expressing a disialoganglioside antigen GD2 was designed, synthesized and characterized. A polymer conjugate of an antitumor drug doxorubicin with a N-(2-hydroxypropyl)methacrylamide-based copolymer was specifically targeted against GD2 antigen-positive tumor cells using a recombinant single chain fragment (scFv) of an anti-GD2 monoclonal antibody. The targeting protein ligand was attached to the polymer-drug conjugate either via a covalent bond between the amino groups of the protein using a traditional nonspecific aminolytic reaction with a reactive polymer precursor or via a noncovalent but highly specific interaction between bungarotoxin covalently linked to the polymer and the recombinant scFv modified with a C-terminal bungarotoxin-binding peptide. The GD2 antigen binding activity and GD2-specific cytotoxicity of the targeted noncovalent polymer-scFv complex proved to be superior to the covalent polymer-scFv conjugate.

• MeSH
• antitumorózní látky aplikace a dávkování   chemie   farmakologie   MeSH
• bungarotoxiny chemie   MeSH
• buňky 3T3 MeSH
• doxorubicin aplikace a dávkování   chemie   farmakologie   MeSH
• gangliosidy imunologie   MeSH
• jednořetězcové protilátky chemie   imunologie   MeSH
• kyseliny polymethakrylové chemie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanokonjugáty chemie   MeSH
• proliferace buněk účinky léků   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• bungarotoxiny MeSH
• doxorubicin MeSH
• Duxon MeSH Prohlížeč
• ganglioside, GD2 MeSH Prohlížeč
• gangliosidy MeSH
• jednořetězcové protilátky MeSH
• kyseliny polymethakrylové MeSH
• nanokonjugáty MeSH

The kinetics of the phasic synchronous and delayed asynchronous release of acetylcholine quanta was studied at the neuromuscular junctions of aging rats from infant to mature animals at various frequencies of rhythmic stimulation of the motor nerve. We found that in infants 6 (P6) and 10 (P10) days after birth a strongly asynchronous phase of quantal release was observed, along with a reduced number of quanta compared to the synapses of adults. The rise time and decay of uni-quantal end-plate currents were significantly longer in infant synapses. The presynaptic immunostaining revealed that the area of the synapses in infants was significantly (up to six times) smaller than in mature junctions. The intensity of delayed asynchronous release in infants increased with the frequency of stimulation more than in adults. A blockade of the ryanodine receptors, which can contribute to the formation of delayed asynchronous release, had no effect on the kinetics of delayed secretion in the infants unlike synapses of adults. Therefore, high degree of asynchrony of quantal release in infants is not associated with the activity of ryanodine receptors and with the liberation of calcium ions from intracellular calcium stores.

• Klíčová slova
• Developing neuromuscular junction, Kinetics of quantum release, Ryanodine receptors, Synaptic latency,
• MeSH
• bungarotoxiny farmakokinetika   MeSH
• elektrická stimulace MeSH
• krysa rodu Rattus MeSH
• kyselina gallová analogy a deriváty   farmakokinetika   MeSH
• nervosvalové spojení účinky léků   růst a vývoj   metabolismus   MeSH
• neurotransmiterové látky metabolismus   MeSH
• nikotinové receptory metabolismus   MeSH
• novorozená zvířata MeSH
• reakční čas fyziologie   MeSH
• ryanodin farmakokinetika   MeSH
• synaptické potenciály fyziologie   MeSH
• synaptofysin metabolismus   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate MeSH Prohlížeč
• bungarotoxiny MeSH
• kyselina gallová MeSH
• neurotransmiterové látky MeSH
• nikotinové receptory MeSH
• ryanodin MeSH
• synaptofysin MeSH

OBJECTIVES: Our previous study showed that administration of nicotine is capable to protect the neurons of hippocampus against the kainic acid induced damage. Here we tested the hypotheses that multiple nicotine administration would prevent the effects of kainic acid on neuronal nicotinic receptor subtypes densities (α-bungarotoxin sensitive and α-bungarotoxin insentive) and on hippocampal cell degeneration. METHODS: Radioligand binding study was used to detect the particular nAChR subtypes densities. Two histochemical methods (bis-benzimide staining and Fluoro-Jade B dye) were used to detect and evaluate neuronal degeneration. RESULTS: Our study shows that: a) kainic acid single administration increased the number of α-bungarotoxin insentive nicotinic receptors, b) nicotine was able to prevent such changes, c) repeated nicotine administration is capable to attenuate the damage of CA1 and CA3 areas of the hippocampus. No effect on α-bungarotoxin sentive nicotinic receptors was observed. Our data therefore reveal the importance of α-bungarotoxin insentive nicotinic receptors in the response to kainite and the ability of nicotine to prevent such changes both in the cell degeneration and in number of receptors. CONCLUSION: Nicotine administration influences α-bungarotoxin insensitive receptors and repeated administration is capable to protect against toxicity caused by kainic acid in hippocampal area.

• MeSH
• agonisté excitačních aminokyselin farmakologie   MeSH
• bungarotoxiny metabolismus   MeSH
• hipokampus cytologie   MeSH
• krysa rodu Rattus MeSH
• kyselina kainová farmakologie   MeSH
• neurony cytologie   účinky léků   patologie   MeSH
• neuroprotektivní látky farmakologie   MeSH
• nikotin farmakologie   MeSH
• nikotinové receptory metabolismus   MeSH
• nikotinoví agonisté farmakologie   MeSH
• potkani Wistar MeSH
• protein - isoformy metabolismus   MeSH
• radioligandová zkouška MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté excitačních aminokyselin MeSH
• bungarotoxiny MeSH
• kyselina kainová MeSH
• neuroprotektivní látky MeSH
• nikotin MeSH
• nikotinové receptory MeSH
• nikotinoví agonisté MeSH
• protein - isoformy MeSH

A new comparative characteristic of endplate microphysiology has been introduced. It is the feasibility of receptors to become desensitised as demonstrated on two frog species, Rana temporaria and Rana ridibunda: the decay times (tau(MEPC)) of single quantum miniature endplate currents (MEPCs) in the sartorius muscles of both species were about 1 ms and were not affected by the desensitisation-promoting agent proadifen when AChE was active. However, when the desensitisation was induced by anticholinesterase neostigmine and promoted by proadifen, the prolongation of tau(MEPC) from 1 ms was almost twice as great in Rana temporaria (tau(MEPC) = 4.4 ms) than in Rana ridibunda (tau(MEPC) = 3.1). This indicates that desensitisation reduces the number of available receptors and lowers the number of available ACh molecules for repetitive binding by trapping them by desensitised, high-affinity receptors significantly more in Rana ridibunda than in Rana temporaria. The application of proadifen, a promoter of desensitisation, decreased the prolongation of MEPCs in both species, but this shortening was more rapid in Rana ridibunda than in Rana temporaria. It is concluded that the desensitisation-induced reduction in the density, and the number of postsynaptic receptors is significantly higher at Rana ridibunda than in Rana temporaria endplates.

• MeSH
• bungarotoxiny farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• druhová specificita MeSH
• inhibitory enzymů farmakologie   MeSH
• kosterní svaly účinky léků   metabolismus   MeSH
• neostigmin farmakologie   MeSH
• nervosvalová ploténka účinky léků   fyziologie   MeSH
• neuroplasticita účinky léků   fyziologie   MeSH
• proadifen farmakologie   MeSH
• Rana ridibunda MeSH
• Rana temporaria MeSH
• receptory cholinergní účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bungarotoxiny MeSH
• cholinesterasové inhibitory MeSH
• inhibitory enzymů MeSH
• neostigmin MeSH
• proadifen MeSH
• receptory cholinergní MeSH