The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Etienne C Hirsch - One of the best experts on this subject based on the ideXlab platform.
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caspase 3 activation in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp treated mice
Movement Disorders, 2001Co-Authors: Helene Turmel, Andreas Hartmann, Karine Parain, Aicha Douhou, Anu Srinivasan, Yves Agid, Etienne C HirschAbstract:In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson's disease (PD), dopaminergic (DA) neurons have been shown to die by apoptosis. Moreover, recent postmortem and in vitro results have indicated that apoptotic cell death induced by 1-methyl-4-phenylpyridinium (MPP+) may be mediated by caspase-3. To establish whether caspase-3 activation may indeed play a role in an in vivo model of PD, we studied caspase-3 activation in C57Bl/6 mice subchronically intoxicated with MPTP. We show that caspase-3 activation peaks early, at days 1 and 2 after the end of MPTP intoxication. In contrast, pycnotic neurons persist until day 7 postintoxication, indicating that caspase-3 activation is an early and transient phenomenon in apoptotic death of DA neurons. We further demonstrate that loss of tyrosine hydroxylase (TH) immunoreactivity in this model is indeed due to cell loss rather than to loss of TH protein expression. We conclude that mice subchronically intoxicated with MPTP represent a valid PD model to study and manipulate caspase activation in vivo. © 2001 Movement Disorder Society.
Ted M Dawson - One of the best experts on this subject based on the ideXlab platform.
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poly adp ribose polymerase activation mediates 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp induced parkinsonism
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Allen S Mandir, Serge Przedborski, Vernice Jacksonlewis, Zhaoqi Wang, Cynthia M Simbulanrosenthal, Mark E Smulson, Brian E Hoffman, Daniel Guastella, Valina L Dawson, Ted M DawsonAbstract:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson’s disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson’s disease.
Ricardo Menegatti - One of the best experts on this subject based on the ideXlab platform.
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Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects
Naunyn-Schmiedeberg's Archives of Pharmacology, 2019Co-Authors: Ricardo Menegatti, Gustavo Rodrigues Pedrino, Flávio S. Carvalho, Luciano M. Lião, Bianca Villavicencio, Hugo Verli, Aline A. Mourão, Carlos H. Xavier, Carlos H. Castro, Octavio L. FrancoAbstract:The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1 H -pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.
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anti nociceptive and anti inflammatory activities of 4 1 phenyl 1h pyrazol 4 yl methyl 1 piperazine carboxylic acid ethyl ester a new piperazine derivative
Pharmacology Biochemistry and Behavior, 2015Co-Authors: Daiany P B Silva, Ricardo Menegatti, Iziara Ferreira Florentino, Lanussy Porfiro De Oliveira, Roberta Campos Lino, Pablinny Moreira Galdino, Elson Alves CostaAbstract:Abstract Piperazine compounds possess anti-infective, anti-carcinogenic, anxiolytic, hypotensive, anti-hypertensive and vasorelaxant properties and are attractive candidates for the development of new analgesic and anti-inflammatory drugs. This study investigates the anti-nociceptive and anti-inflammatory effects of piperazine derivative 4-[(1-phenyl-1H-pyrazol-4-yl) methyl]1-piperazine carboxylic acid ethyl ester (LQFM-008) and the involvement of the serotonergic pathway. In the formalin test, treatments with LQFM-008 (15 and 30 mg/kg p.o.) reduced the licking time in both neurogenic and inflammatory phases of this test. In the tail flick and hot plate tests, LQFM008 treatment (15 and 30 mg/kg p.o.) increased latency to thermal stimulus, suggesting the involvement of central mechanisms in the anti-nociceptive effect of LQFM-008. In the carrageenan-induced paw edema test, LQFM-008 (p.o.) at the doses of 15 and 30 mg/kg reduced the edema at all tested time points, while the dose of 7.5 mg/kg reduced the edema only for the first hour. LQFM-008 (30 mg/kg p.o.) reduced both cell migration and protein exudation in the carrageenan-induced pleurisy test. Furthermore, pre-treatment with NAN-190 (0.6 mg/kg i.p.) and PCPA (100 mg/kg i.p.) antagonized the anti-nociceptive effect of LQFM-008 in both phases of the formalin test. Our data suggest that LQFM-008 possesses anti-inflammatory and anti-nociceptive effects mediated through the serotonergic pathway.
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hypotensive and antihypertensive potential of 4 1 phenyl 1h pyrazol 4 yl methyl 1 piperazine carboxylic acid ethyl ester a piperazine derivative
Life Sciences, 2014Co-Authors: James Oluwagbamigbe Fajemiroye, Elson Alves Costa, Pablinny Moreira Galdino, Nathalia Oda Amaral, Elaine Fernanda Da Silva, Thiago Sardinha De Oliveira, Paulo Cesar Ghedini, Jordan K Zjawiony, Gustavo Rodrigues Pedrino, Ricardo MenegattiAbstract:Abstract Aims Clinical complaints on the first-line of cardiovascular medications make continuous search for new drugs a necessity. This study evaluated the cardiovascular effects and mechanism of 4-[(1-phenyl-1 H -pyrazol-4-yl)methyl]1-piperazine carboxylic acid ethyl ester (LQFM008). Main methods Normotensive male Wistar or spontaneously hypertensive rats (anesthetized or conscious) were used to evaluate the effect of LQFM008 on the mean arterial pressure (MAP), heart rate (HR), arterial blood flow (ABF), arterial vascular conductance (AVC), baroreflex effectiveness index (BI), systolic blood pressure (SBP), diastolic blood pressure (DBP) and vascular function. Key findings In anesthetized normotensive rats, LQFM008 (7.3, 14.3 or 28.6 μmol/kg, iv) reduced MAP (− 21.1 ± 2.7; − 23.9 ± 4.7 or − 32.4 ± 8.3 mm Hg, respectively) and AVC (22%, 32% or 38%) in a dose-dependent manner. LQFM008 elicited a temporal reduction in the SBP and DBP without changes to the BI of conscious normotensive rats. In hypertensive rats, LQFM008 (7.3, 14.3 or 28.6 μmol/kg, iv) reduced MAP ( −2.3 ± 2.6; − 29.3 ± 2.7 or −38.4 ± 2.8 mmHg, respectively) and increased HR (1.6 ± 3.7; 15.4 ± 4.9 or 25.5 ± 6.2 bmp, respectively) in a dose-dependent manner. A week of oral administration of LQFM008 47.7 μmol/kg elicited a temporal reduction in SBP of hypertensive rats. Pretreatments with atropine, WAY-100635 or L-NAME blocked the effect of LQFM008. In addition, LQFM008-induced endothelium-dependent vascular relaxation was inhibited by L-NAME. Significance Our findings showed hypotensive, antihypertensive and vasorelaxant effects of LQFM008 and suggest the participation of nitric oxide, 5-HT1A and muscarinic receptors.
Helene Turmel - One of the best experts on this subject based on the ideXlab platform.
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caspase 3 activation in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp treated mice
Movement Disorders, 2001Co-Authors: Helene Turmel, Andreas Hartmann, Karine Parain, Aicha Douhou, Anu Srinivasan, Yves Agid, Etienne C HirschAbstract:In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson's disease (PD), dopaminergic (DA) neurons have been shown to die by apoptosis. Moreover, recent postmortem and in vitro results have indicated that apoptotic cell death induced by 1-methyl-4-phenylpyridinium (MPP+) may be mediated by caspase-3. To establish whether caspase-3 activation may indeed play a role in an in vivo model of PD, we studied caspase-3 activation in C57Bl/6 mice subchronically intoxicated with MPTP. We show that caspase-3 activation peaks early, at days 1 and 2 after the end of MPTP intoxication. In contrast, pycnotic neurons persist until day 7 postintoxication, indicating that caspase-3 activation is an early and transient phenomenon in apoptotic death of DA neurons. We further demonstrate that loss of tyrosine hydroxylase (TH) immunoreactivity in this model is indeed due to cell loss rather than to loss of TH protein expression. We conclude that mice subchronically intoxicated with MPTP represent a valid PD model to study and manipulate caspase activation in vivo. © 2001 Movement Disorder Society.
Clivel G Charlton - One of the best experts on this subject based on the ideXlab platform.
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1 methyl 4 phenyl pyridinium increases s adenosyl l methionine dependent phospholipid methylation
Pharmacology Biochemistry and Behavior, 2001Co-Authors: Clivel G CharltonAbstract:Abstract 1-Methyl-4-phenyl-pyridinium (MPP+) and S-adenosyl- l -methionine (SAM) cause Parkinson's disease (PD)-like changes. SAM and MPP+ require their charged S-methyl and N-methyl groups, so the PD-like symptoms may be related to their ability to modulate the methylation process. The SAM-dependent methylation of phosphatidylethanolamine (PTE) to produce phosphatidylcholine (PTC), via phosphatidylethanolamine-N-methyltransferase (PEMT), and the hydrolysis of PTC to form lyso-PTC, a cytotoxic agent, are potential loci for the action of MPP+. In this study, the effects of MPP+ on the methylation of PTE to PTC and the production of lyso-PTC were determined. The results showed that SAM increased PTC and lyso-PTC. The rat striatum showed the highest PEMT activity and lyso-PTC formation, which substantiate with the fact that the striatum is the major structure that is affected in PD. MPP+ significantly enhanced PEMT activity and the formation of lyso-PTC in the rat liver and brain. MPP+ increased the affinity and the Vmax of PEMT for SAM. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effect was lesser and inhibited by deprenyl (MAO-B inhibitor). The nor-methyl analogs of MPP+ were inactive, but some of the charged analogs of MPP+ showed comparable effects to those of MPP+. Lyso-PTC that can be increased by SAM and MPP+ caused severe impairments of locomotor activities in rats. These results indicate that SAM and MPP+ have complementary effects on phospholipid methylation. Thus, SAM-induced hypermethylation could be involved in the etiology of PD and an increase of phospholipid methylation could be one of the mechanisms by which MPP+ causes parkinsonism.
