1,721,031 research outputs found
“Premio cultura per meriti scientifici” Congresso Nazionale della Lega Italiana contro l’Epilessia
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Muteins of the CGRP 1-7 peptide fragment and use thereof as nicotinic neuronal receptor enhancers
No full textDonepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones
No full text1 The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)-mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch-clamp recording technique in slice preparations. 2 Donepezil (10-100 muM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice. 3 The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist. 4 Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent. 5 Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine-induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor
Methamidophos transiently inhibits neuronal nicotinic receptors of rat substantia nigra dopaminergic neurons via open channel block
No full textThe use of acetylcholinesterase (AChE) inhibitors is the primary therapeutic strategy in the treatment of Alzheimer's disease. However, these drugs have been reported to have effects beyond the simple stimulation of neuronal acetylcholine receptors (AChRs) by elevated acetylcholine (ACh), interfering directly with the nAChR. Therefore, a pure pharmacological blockade of AChE is not usually obtained. In this study, the patch-clamp technique was utilized to determine the effects of methamidophos, a pesticide that is considered a selective AChE inhibitor, on nAChRs of substantia nigra dopaminergic neurons. In spite of the fact that methamidophos has been reported to be devoid of direct nicotinic actions, our main observation was that it selectively and reversibly blocked nAChR responses, without directly affecting the holding current. Methamidophos produced a downward shift in the dose response curve for nicotine; the mechanism accounting for this non-competitive antagonism was open channel block, in view of its voltage dependence. Pre-treatment with vesamicol did not prevent the reduction of nicotine-induced currents, indicating that the effect on nAChRs was independent from the activity of methamidophos as a cholinesterase inhibitor. Our results conclude that methamidophos has a complex blocking action on neuronal nAChRs that is unlinked to the inhibition of AChE. Therefore, it should not be considered a selective AChE inhibitor and part of its toxic effects could reside in an interference with the nicotinic neurotransmission. (C) 2004 Elsevier Ireland Ltd. All rights reserved
Chemokines and chemokine receptors in the nervous system Rome, 27/28 October, 2007
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Chemokines and chemokine receptors in the nervous system Rome, 24/25 October, 2009, 2nd workshop
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Enhancement of neuronal nicotinic receptor activity of rat chromaffin cells by a novel class of peptides.
No full textThe N-terminal 1-7 fragment of the neuropeptide CGRP inhibits neuronal nicotinic acetylcholine receptors (nAChRs) of rat chromaffin cells. To identify the structural motif responsible for this action, we investigated the effects of shorter CGRP fragments on patch-clamped rat chromaffin cells in culture. CGRP(1-6) evoked no direct change in baseline current or input conductance, but it strongly potentiated inward currents induced by very fast, non-desensitizing applications of nicotine. Potentiation was use independent and present even when coapplied with nicotine. The action of CGRP(1-6) was voltage independent and agonist independent. Because equimolar concentrations of CGRP(1-6) and CGRP(1-7) left nicotine-induced submaximal currents unchanged, these peptides presumably acted via a similar site through which they generated opposite effects. This observation also suggests that a single amino acid deletion could transform a peptide antagonist into a potentiating one. Deleting one amino acid from the COO- end of the CGRP(1-6) sequence yielded CGRP(1-5), which retained smaller potentiating activity. Even the CGRP(1-4) fragment possessed slight potentiation, which was lost with CGRP(1-3). CGRP(1-6) preferentially potentiated small over large responses to nicotine. One possibility is that CGRP(1-6) interacted with nAChRs like an allosteric modulator (e.g., physostigmine). Coapplication of enhancing concentrations of physostigmine and CGRP(1-6) led to linear summation of the individual effects, while CGRP(1-6) could partly reverse the depression by a large concentration of physostigmine. These data indicate functionally distinct sites of action for CGRP(1-6) and physostigmine. Potentiation of nicotinic receptors by CGRP(1-6) and its derivatives suggests them to be a new class of molecules enhancing activity mediated by nAChRs
Calibration of agonist concentrations applied by pressure pulses or via rapid solution exchanger.
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