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A novel physiological property of snake bradykinin-potentiating peptides-Reversion of MK-801 inhibition of nicotinic acetylcholine receptors

NERY, Arthur A.; TRUJILLO, Cleber A.; LAMEU, Claudiana; KONNO, Katsuhiro; OLIVEIRA, Vitor; CAMARGO, Antonio C. M.; ULRICH, Henning; HAYASHI, Mirian A. F.
Fonte: ELSEVIER SCIENCE INC Publicador: ELSEVIER SCIENCE INC
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.958293%
The first naturally occurring angiotensin-converting enzyme (ACE) inhibitors described are pyroglutamyl proline-rich oligopeptides, found in the venom of the viper Bothrops jararaca, and named as bradykinin-potentiating peptides (BPPs). Biochemical and pharmacological properties of these peptides were essential for the development of Captopril, the first active site-directed inhibitor of ACE, currently used for the treatment of human hypertension. However, a number of data have suggested that the pharmacological activity of BPPs could not only be explained by their inhibitory action on enzymatic activity of somatic ACE. In fact, we showed recently that the strong and long-lasting anti-hypertensive effect of BPP-10c [

Effects of MK-801 and amphetamine treatments on allergic lung inflammatory response in mice

Hamasato, Eduardo Kenji; Oliveira, Ana Paula Ligeiro de; Franco, Adriana Lino dos Santos; Ribeiro, Alison; Paula, Viviane Ferraz de; Peron, Jean Pierre Schatzmann; Damazo, Amílcar Sabino; Lima, Wothan Tavares de; Neto, João Palermo
Fonte: Elsevier Science; Amsterdam Publicador: Elsevier Science; Amsterdam
Tipo: Artigo de Revista Científica
Português
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37.419067%
Glutamate acts as a neurotransmitter within the Central Nervous System (CNS) and modifies immune cell activity. In lymphocytes, NMDA glutamate receptors regulate intracellular calcium, the production of reactive oxygen species and cytokine synthesis. MK-801, a NMDA receptor open-channel blocker, inhibits calcium entry into mast cells, thereby preventing mast cell degranulation. Several lines of evidence have shown the involvement of NMDA glutamate receptors in amphetamine (AMPH)-induced effects. AMPH treatment has been reported to modify allergic lung inflammation. This study evaluated the effects of MK-801 (0.25mg/kg) and AMPH (2.0mg/kg), given alone or in combination, on allergic lung inflammation in mice and the possible involvement of NMDA receptors in this process. In OVA-sensitized and challenged mice, AMPH and MK-801 given alone decreased cellular migration into the lung, reduced IL-13 and IL10 levels in BAL supernatant, reduced ICAM-1 and L-selectin expression in granulocytes in the BAL and decreased mast cell degranulation. AMPH treatment also decreased IL-5 levels. When both drugs were administered, treatment with MK-801 reversed the decrease in the number of eosinophils and neutrophils induced by AMPH in the BAL of OVA-sensitized and challenged mice as well as the effects on the expression of L-selectin and ICAM-1 in granulocytes...

Participação glutamatérgica nos efeitos induzidos pela anfetamina na resposta inflamatória alérgica pulmonar de camundongos; Glutamatergic involvement in amphetamine-induced effects on pulmonary allergic inflammatory response in mice

Hamasato, Eduardo Kenji
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 06/09/2011 Português
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O objetivo do presente estudo foi avaliar a participação do sistema glutamatérgico nos efeitos induzidos pela anfetamina em camundongos sensibilizados e desafiados com ovalbumina, através do tratamento prévio com MK-801, um antagonista de receptores glutamatérgicos NMDA. Em relação aos animais tratados apenas com anfetamina, observamos que o tratamento prévio com MK-801: 1) reverteu a diminuição no número de leucócitos totais bem como o número de eosinófilos e neutrófilos no lavado broncoalveolar (LBA); 2) reverteu a diminuição da porcentagem de expressão das moléculas L-selectina e ICAM-1 em granulócitos do LBA; 3) reverteu a diminuição das citocinas IL-10 e IL-13 no sobrenadante do LBA; 4) reverteu a diminuição na contração da traquéia; 5) reverteu a desgranulação de mastócitos pulmonares; 6) não alterou a produção de IgE total e IgE-OVA; 7) não reduziu os níveis de corticosterona plasmáticos. Tomados em seu conjunto, quer nos parecer que os efeitos induzidos pela anfetamina implicam na ativação do sistema glutamatérgico via receptores NMDA. Possivelmente, as diferenças dos efeitos do MK-801, da anfetamina ou a combinação de fármacos se devam a uma ativação (modulação) diferenciada sobre o eixo hipotálamo pituitária adrenal (HPA) e/ou sistema nervoso autônomo simpático (SNAS) o que poderia explicar os efeitos opostos observados na resposta inflamatória alérgica pulmonar de camundongos.; The aim of this study was to evaluate the involvement of the glutamatergic system in the effects induced by amphetamine in mice OVA-sensitized and challenged by the pretreatment with MK-801...

Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels.

Huettner, J E; Bean, B P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1988 Português
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Whole-cell and single-channel recording techniques were used to study the action of the anticonvulsant drug MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]- cyclohepten-5,10-imine maleate) on responses to excitatory amino acids in rat neocortical neurons in cell culture. MK-801 caused a progressive, long-lasting blockade of current induced by N-methyl-D-aspartate (N-Me-D-Asp). However, during the time that N-Me-D-Asp responses were inhibited, there was no effect on responses to quisqualate or kainate, suggesting that N-Me-D-Asp receptors and kainate/quisqualate receptors open separate populations of ion channels. Binding and unbinding of MK-801 seems to be possible only if the N-Me-D-Asp-operated channel is in the transmitter-activated state: MK-801 was effective only when applied simultaneously with N-Me-D-Asp, and recovery from MK-801 blockade was speeded by continuous exposure to N-Me-D-Asp [time constant (tau) approximately equal to 90 min at -70 to -80 mV]. Recovery from block during continuous application of N-Me-D-Asp was strongly voltage dependent, being faster at positive potentials (tau approximately equal to 2 min at +30 mV). Mg2+, which is thought to block the N-Me-D-Asp-activated ion channel, inhibited blockade by MK-801 at negative membrane potentials. In single-channel recordings from outside-out patches. MK-801 greatly reduced the channel activity elicited by application of N-Me-D-Asp but did not significantly alter the predominant unitary conductance. Consistent with an open-channel blocking mechanism...

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.

Wong, E H; Kemp, J A; Priestley, T; Knight, A R; Woodruff, G N; Iversen, L L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1986 Português
Relevância na Pesquisa
27.447866%
The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine...

Cholinesterase Inhibitors Ameliorate Behavioral Deficits Induced by MK-801 in Mice

Csernansky, John G.; Martin, Maureen; Shah, Renu; Bertchume, Amy; Colvin, Jenny; Dong, Hongxin
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2005 Português
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Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the non-competitive N-methyl-daspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 mg/kg or 0.10mg/kg) or saline was administered i.p. 20 minutes prior to behavioral testing over a total of 14 days. Thirty minutes prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (i.e., physostigmine - 0.03, 0.10, or 0.30 mg/kg, donepezil - 0.10, 0.30, or 1.00 mg/kg, or galantamine - 0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: 1) spatial reversal learning, 2) locomotion, 3) fear conditioning and 4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory...

Pharmacological profiles of a novel opioid receptor-like1 (ORL1) receptor antagonist, JTC-801

Yamada, Hideki; Nakamoto, Hiromitsu; Suzuki, Yasunori; Ito, Takao; Aisaka, Kazuo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/2002 Português
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Pharmacological effects of a novel opioid receptor-like1 (ORL1) receptor antagonist, [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride] (JTC-801), were examined in in vitro and in vivo.JTC-801 inhibited the binding of [3H]-nociceptin to human ORL1 receptors expressed in HeLa cells with a Ki value of 44.5 nM.JTC-801 completely antagonized the suppression of nociceptin on forskolin-induced accumulation of cyclic AMP (IC50 : 2.58 μM) using ORL1 receptor expressing HeLa cells in vitro.In in vivo, when given intravenously at dosages of 0.01 mg kg−1 and above, or orally at dosages 1 mg kg−1 and above, JTC-801 antagonized the nociceptin-induced allodynia in mice.Effects of JTC-801 on various nociceptive models were examined. In mouse hot-plate test, JTC-801 prolonged escape response latency (ERL) to exposed heat stimulus with minimum effective doses (MED) of 0.01 mg kg−1 by i.v. or 1 mg kg−1 by p.o.In the rat formalin test, JTC-801 reduced both the first and second phases of the nociceptive response with MED of 0.01 mg kg−1 by i.v. administration or 1 mg kg−1 by p.o. administration. This anti-nociceptive action of JTC-801 was not inhibited by naloxone (10 mg kg−1...

Quantitative autoradiography of [3H]-MK-801 binding sites in mammalian brain.

Bowery, N. G.; Wong, E. H.; Hudson, A. L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1988 Português
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27.419067%
1. An in vitro receptor autoradiography procedure is described for visualizing binding sites for the excitatory amino acid antagonist radiolabelled MK-801, in rat and gerbil brain sections. 2. Ten micron sections were labelled by incubation at room temperature for 20 min in 30 nM [3H]-MK-801. This was followed by 2 rinses for 20 s in fresh buffer solution. Specifically bound ligand determined with 100 microM unlabelled MK-801 amounted to 55-60% of total. 3. Phencyclidine, (+/-)-SKF 10047, ketamine and 2-aminophosphonovaleric acid (APV) (all 100 microM) prevented the specific binding of [3H]-MK-801. L-Glutamate and N-methyl D-aspartate (NMDA) (100 microM) had no effect. However, L-glutamate prevented the inhibition by APV. 4. The highest concentrations of [3H]-MK-801 binding sites occurred in the hippocampal formation, cerebral cortex, olfactory bulb and thalamus. Very low levels were detected in the brain stem and cerebellum. 5. The distribution of [3H]-MK-801 binding sites was comparable to that of NMDA sites and phencyclidine sites (labelled with [3H]-TCP) but not with high-affinity sigma sites labelled with [3H]-3-PPP. 6. The density of [3H]-MK-801 binding sites in the gerbil hippocampus was examined 1, 2, 6 and 22 days after unilateral carotid artery occlusion for 10 min. Only at 6 and 22 days was the binding reduced (by 36% and 46% respectively) in the CA1 region whereas a significant neuronal loss was apparent at day 2. In CA2 a decrease in binding was only evident at day 22. 7. These results indicate that binding sites for [3H]-MK-801 can be detected in mammalian brain sections by receptor autoradiography. Their distribution supports an association with the NMDA receptor complex and the loss in the hippocampus after carotid artery occlusion indicates their presence on pyramidal cells is vulnerable to ischaemic insult.

Inhibition of [3H]-(+)-MK 801 binding to rat brain sections by CPP and 7-chlorokynurenic acid: an autoradiographic analysis.

Tacconi, S.; Ratti, E.; Marien, M. R.; Gaviraghi, G.; Bowery, N. G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1993 Português
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27.419067%
1. The regional binding of [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d)cyclohepten-5,10-imine maleate ([3H]-(+)-MK 801) to sections of rat brain was measured by an in vitro quantitative autoradiographic technique. A heterogeneous distribution of binding sites was observed. 2. High values of binding were detected in the hippocampal formation and cerebral cortex, while very low binding was found in cerebellum. [3H]-(+)-MK 801 binding was not detectable in white matter tracts or in the brain stem. 3. [3H]-(+)-MK 801 binding was inhibited by increasing concentrations of both 7-chlorokynurenate (1-1000 microM) and ((+)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) (0.1-100 microM). High concentrations of both drugs were able to inhibit completely specific [3H]-(+)-MK 801 binding. 4. IC50 values calculated for both 7-chlorokynurenate and CPP-induced [3H]-(+)-MK 801 binding inhibition were similar in all brain regions analyzed. 5. The inhibitory action of 7-chlorokynurenate and that of CPP on [3H]-(+)-MK 801 binding were reversed by addition of glycine and glutamate respectively. 6. It is concluded that activation of glycine and N-methyl-D-aspartate (NMDA) receptors is obligatory for the binding of [3H]-(+)-MK 801 to occur in all of the brain regions examined in the present study. Furthermore...

The H3 Antagonist, Ciproxifan, Alleviates the Memory Impairment but Enhances the Motor Effects of MK-801 (Dizocilpine) in Rats.

Bardgett, Mark E.; Points, Megan; Kleier, Jennifer; Blankenship, Meredith; Griffith, Molly S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
27.419067%
Antagonists of H3-type histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of antipsychotic activity in normal animals. The present study determined if a prototypical H3 antagonist, ciproxifan, could reverse the behavioral effects of MK-801, a drug used in animals to mimic the hypoglutamatergic state suspected to exist in schizophrenia. Four behaviors were chosen for study, locomotor activity, ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a subcutaneous injection of ciproxifan or vehicle followed twenty minutes later by a subcutaneous injection of MK-801 or vehicle. Three doses of MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of MK-801, but suppressed the effect of the high dose. Ciproxifan (3.0 mg/kg) enhanced the effects of MK-801 (0.1 & 0.3 mg/kg) on fine movements and ataxia. Deficits in PPI were observed after treatment with MK-801 (0.05 & 0.1 mg/kg), but ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by MK-801 (0.1 mg/kg) at a longer delay...

Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Holahan, Matthew R.; Madularu, Dan; McConnell, Erin M.; Walsh, Ryan; DeRosa, Maria C.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 13/07/2011 Português
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Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease.

Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

McKay, Sean; Bengtson, C. Peter; Bading, Hilmar; Wyllie, David J.A.; Hardingham, Giles E.
Fonte: Pergamon Press Publicador: Pergamon Press
Tipo: Artigo de Revista Científica
Publicado em /11/2013 Português
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MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents...

Comparison of a Resonant Mirror Biosensor (IAsys) and a Quartz Crystal Microbalance (QCM) for the Study on Interaction between Paeoniae Radix 801 and Endothelin-1

Huang, Jiadong; Lin, Qing; Yu, Jinghua; Ge, Shenguang; Li, Jing; Yu, Min; Zhao, Zixia; Wang, Xinsheng; Zhang, Xiuming; He, Xiaorui; Yuan, Liang; Yin, Huijun; Osa, Tetsuo; Chen, Keji; Chen, Qiang
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
Publicado em 15/12/2008 Português
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A resonant mirror biosensor, IAsys, and a quartz crystal microbalance (QCM) are known independently as surface sensitive analytical devices capable of label-free and in situ bioassays. In this study, an IAsys and a QCM are employed for a new study on the action mechanism of Paeoniae Radix 801 (P. radix 801) by detecting the specific interaction between P. radix 801 and endothelin-1 (ET-1). In the experiments, ET-1 was immobilized on the surfaces of the IAsys cuvette and the QCM substrate by surface modification techniques, and then P. radix 801 solution was contacted to the cuvette and the substrate, separately. Then, the binding and interaction process between P. radix 801 and ET-1 was monitored by IAsys and QCM, respectively. The experimental results showed that P. radix 801 binds ET-1 specifically. The IAsys and QCM response curves to the ET-1 immobilization and P. radix 801 binding are similar in reaction process, but different in binding profiles, reflecting different resonation principles. Although both IAsys and QCM could detect the interaction of P. radix 801 and ET-1 with high reproducibility and reliability through optimization of the ET-1 coating, the reproducibility and reliability obtained by IAsys are better than those obtained by QCM...

Avaliação do uso do antagonista dos receptores NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de lesão pulmonar aguda

Cunha, Aline Andrea da
Fonte: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre Publicador: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
27.509924%
A lesão pulmonar aguda (LPA) é uma síndrome caracterizada por inflamação pulmonar aguda e persistente, com edema pulmonar devido ao aumento da permeabilidade vascular. Na LPA ocorre uma lesão do epitélio alveolar e do endotélio capilar por diferentes mediadores pró-inflamatórios, principalmente, pelas citocinas liberadas em resposta à grande variedade de insultos. A geração de radicais livres (RLs) é outro importante mecanismo de lesão utilizado pelos neutrófilos, que são capazes de gerar muitas das alterações encontradas na LPA. Sabe-se que a produção endógena de glutamato estimula uma variedade de mediadores inflamatórios, incluindo metabólitos do ácido araquidônico, RLs e óxido nítrico (NO). O primeiro relato de que os receptores NMDA poderiam estar envolvidos na fisiopatologia pulmonar ocorreu através da demonstração que o tratamento com um inibidor seletivo desse receptor (MK-801) prevenia o edema pulmonar provocado pelo aumento de NMDA instilado na traquéia de ratos sob ventilação mecânica.O objetivo deste trabalho foi avaliar o uso do antagonista de receptor NMDA (MK- 801) como protetor no dano oxidativo em modelo experimental de LPA. Foram utilizados ratos Wistar, machos. Os animais foram divididos em 4 grupos experimentais: Grupo 1: Injeção intratraqueal (I. T. ) de 1 mL de solução salina (n=6); grupo 2: Indução da LPA através da injeção de LPS intratraqueal (100 g/100 g de peso corporal) e tratamento com solução salina intraperitoneal (I. P. ) após indução da LPA (n=6); grupo 3: Indução da LPA e tratamento com MK-801 (0. 3 mg/kg I. P. ) após indução da LPA (n=6) e grupo 4: Indução da LPA e tratamento com MK-801 (0. 3 mg/kg I. T. ) após indução da LPA (n=6). Doze horas após o tratamento...

Avaliação do papel do sistema purinérgico e dopaminérgico no efeito antidepressivo promovido por MK-801 em peixe-zebra (Danio rerio)

Souza, Raquel Bohrer da Silva
Fonte: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre Publicador: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
27.605662%
A depressão é uma doença grave, recorrente, caracterizada por anedonia, perda de interesse em atividades diárias, distúrbios do apetite e do sono, concentração reduzida e agitação psicomotora. Os fármacos antidepressivos utilizados atualmente têm um início de ação muito lento, com isso, surge a necessidade de tratamentos de ação rápida. Portanto, há um interesse crescente em antagonistas de receptores NMDA como um alvo para o desenvolvimento de novos fármacos antidepressivos. Considerando-se que os sistemas purinérgicos e dopaminérgicos estão envolvidos na ansiedade, sono e depressão, caracterizamos o papel destas vias de sinalização sobre os efeitos antidepressivos induzidos por MK-801, um antagonista NMDA, em peixe-zebra. Os animais tratados com MK-801 em doses de 5, 10, 15 e 20 μM durante 15, 30 e 60 minutos apresentaram maior permanência na área superior do aquário, em comparação com o grupo controle, indicando um efeito antidepressivo induzido por este composto.Os animais tratados com MK-801 permaneceram até 2 horas na parte superior do aquário quando tratados com 5 μM de MK-801 e 4 horas quando tratados com 20 μM MK-801, retornando aos parâmetros basais após 24 horas de exposição. O tratamento repetido não induziu efeitos cumulativos...

Avaliação do potencial neuroprotetor de fármacos antipsicóticos em alterações bioquímicas, moleculares e comportamentais induzidas por antagonista de receptor NMDA (MK-801) em peixe zebra (Danio rerio)

Bender, Kelly Juliana Seibt
Fonte: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre Publicador: Pontifícia Universidade Católica do Rio Grande do Sul; Porto Alegre
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
27.586426%
A esquizofrenia é uma doença mental grave caracterizada por sintomas positivos, negativos e déficits cognitivos que ainda é pouco compreendida. A redução da neurotransmissão glutamatérgica por antagonistas dos receptores NMDA mimetiza os sintomas da esquizofrenia. Muitos modelos animais têm mostrado sua importância para o estudo dessa doença, e o peixe-zebra tem sido proposto como um modelo promissor para estudar os efeitos in vivo de várias drogas e descobrir novos alvos farmacológicos. Neste estudo caracterizamos a síndrome comportamental produzida pela exposição ao antagonista do receptor NMDA, MK-801, no peixe zebra, e investigamos a capacidade dos fármacos antipsicóticos em reverter estes sintomas. MK-801 (20 μM) aumentou o comportamento locomotor que foi medido pelo número de linhas cruzadas, a distância percorrida e a velocidade média no aquário teste, após 15, 30 e 60 min de exposição. Os antipsicóticos sulpirida, olanzapina e haloperidol reverteram as alterações locomotoras induzidas pelo MK-801 em todos os parâmetros testados, e em doses que administrado isoladamente não tiveram efeito sobre a atividade locomotora. Modelos de interação social e déficits cognitivos em animais pode ser de grande utilidade para o desenvolvimento de novos tratamentos para os sintomas negativos e cognitivos da esquizofrenia. Os resultados mostraram que o MK-801 (5 μM) administrado antes do treino impediu a formação da memória...

Postnatal changes in N-methyl-D-aspartate receptor binding and stimulation by glutamate and glycine of [3H]-MK-801 binding in human temporal cortex.

Slater, P.; McConnell, S. E.; D'Souza, S. W.; Barson, A. J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1993 Português
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1. Homogenates of human infant and adult temporal cortex were used to measure [3H]-TCP and [3H]-MK-801 binding to the N-methyl-D-aspartate (NMDA)-coupled ion channel phencyclidine site. 2. Both [3H]-TCP and [3H]-MK-801 binding increased in infant cortex by > 100% between term and 26 weeks suggesting that the numbers of NMDA receptors increase during postnatal brain development. 3. [3H]-MK-801 binding was measured under non-equilibrium conditions in temporal cortex homogenates with the addition of 100 microM of L-glutamate plus a range of concentrations (0.05 microM-100 microM) of glycine. Glutamate and glycine increased [3H]-MK-801 binding by stimulating NMDA receptors and improving [3H]-MK-801 access to ion channel binding sites; maximum stimulation in adult and infant temporal cortex was achieved with 100 microM glutamate plus 5 microM glycine; a higher concentration of glycine (50 microM) reduced [3H]-MK-801 binding to below maximum. 4. The stimulation by 100 microM glutamate plus 5 microM glycine of [3H]-MK-801 binding in infant temporal cortex was affected by postnatal age. For example, although the stimulation of [3H]-MK-801 binding in 5-6 week infant cortex (236% of basal) was similar to adult cortex (230% of basal), in samples taken from infants aged 5-6 months glycine (plus glutamate) stimulation of [3H]-MK-801 binding (392% of basal) was substantially greater than that measured in adult temporal cortex. 5. The binding of [3H]-glycine to the glycine modulatory site associated with the NMDA receptor in infant cortex also increased with postnatal age by > 100% between term and 26 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK-801: a voltage clamp study on neuronal cells in culture.

Halliwell, R. F.; Peters, J. A.; Lambert, J. J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1989 Português
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1. Some possible molecular mechanisms of action of the anxiolytic, anticonvulsant and neuroprotective agent MK-801 have been examined in 'whole-cell' voltage clamp recordings performed on rat hippocampal and cortical neurones, bovine adrenomedullary chromaffin cells and N1E-115 neuroblastoma cells maintained in cell culture. 2. Transmembrane currents recorded from rat hippocampal and cortical neurones in response to locally applied N-methyl-D-aspartate (NMDA) were antagonized by MK-801 (0.1-3.0 microM). Blockade was use-dependent, and little influenced by transmembrane potential. MK-801 (3 microM) had no effect on currents evoked by kainate (100 microM). 3. The antagonism of NMDA-induced currents by MK-801 was only slowly and incompletely reversed when the cell membrane potential was clamped at -60 mV during washout. Prolonged applications of NMDA at +40, but not -60 mV during washout, markedly accelerated recovery from block. 4. In contrast to MK-801, ketamine (10 microM) blocked NMDA-induced currents in a voltage-dependent manner. Blockade increased with membrane hyperpolarization and was completely reversible upon washout. 5. MK-801 (1-10 microM) produced a voltage- and concentration-dependent block of membrane currents elicited by ionophoretically applied acetylcholine (ACh) recorded from bovine chromaffin cells. The block was readily reversible upon washout. 6. gamma-Aminobutyric acidA (GABAA) receptor-mediated chloride currents of chromaffin cells were unaffected by MK-801 (1-100 microM). In contrast...

Different MK-801 administration schedules induce mild to severe learning impairments in an operant conditioning task: role of buspirone and risperidone in ameliorating these cognitive deficits

Rapanelli, Maximiliano; Frick, Luciana Romina; Bernardez Vidal, Micaela; Zanutto, Bonifacio Silvano
Fonte: Elsevier Publicador: Elsevier
Tipo: info:eu-repo/semantics/article; info:ar-repo/semantics/artículo; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Português
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Blockade of N-methyl-d-aspartate receptor (NMDA) by the noncompetitive NMDA receptor (NMDAR) antagonist MK-801 produces behavioral abnormalities and alterations in prefrontal cortex (PFC) functioning. Due to the critical role of the PFC in operant conditioning task learning, we evaluated the effects of acute, repeated postnatal injections of MK-801 (0.1 mg/kg) on learning performance. We injected Long-Evans rats i.p. with MK-801 (0.1 mg/kg) using three different administration schedules: injection 40 min before beginning the task (during) (n = 12); injection twice daily for six consecutive days prior to beginning the experimental procedures (prior) (n = 12); or twice daily subcutaneous injections from postnatal day 7 to 11 (postnatal) (n = 12). Next, we orally administered risperidone (serotonin receptor 2A and dopamine receptor 2 antagonist, 1 mg/kg) or buspirone (serotonin receptor 1A partial agonist, 10 mg/kg) to animals treated with the MK-801 schedule described above. The postnatal and prior administration schedules produced severe learning deficits, whereas injection of MK-801 just before training sessions had only mild effects on acquisition of an operant conditioning. Risperidone was able to reverse the detrimental effect of MK-801 in the animals that were treated with MK-801 during and prior training sessions. In contrast...

El uso del modelo farmacológico basado en la administración experimental de MK-801, para la revisión y re-definición del sistema límbico en el contexto de la anátomo-patología

Bueno,Adrián Marcelo; de Olmos,Soledad
Fonte: Ciencias Psicológicas Publicador: Ciencias Psicológicas
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/05/2009 Português
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El efecto neurotóxico inducido en el sistema límbico de ratas por el tratamiento agudo con MK-801, afecta a todas las áreas del lóbulo límbico, como la corteza olfatoria, la amígdala baso-lateral, el sistema hipocampal, la corteza del cíngulo y regiones específicas de la corteza frontal e insular (allo-corticales y meso-corticales). En contraste, los núcleos sub-corticales habitualmente incluidos en el sistema límbico, como la amígdala extendida, el sistema estriado-palidal ventral, el área septal, el tálamo y el hipotálamo, no evidencian muerte neuronal. Los resultados anátomo-patológicos sugieren que las áreas del lóbulo límbico comparten características comunes, y soporta la idea de una unidad funcional que es diferente, dentro del sistema límbico, de otras regiones “límbicas” sub-corticales. Esto apoya la consideración de un lóbulo límbico compuesto estrictamente por áreas allo-corticales y meso-corticales del telencéfalo e implica la necesidad de re-definir el clásico y amplio concepto de “sistema límbico”