Publications by authors named "Luis Eduardo Menezes Quintas"

3 Publications

  • Page 1 of 1

The Janus face of ouabain in Na /K -ATPase and calcium signalling in neurons.

Br J Pharmacol 2021 Feb 28. Epub 2021 Feb 28.

Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Na /K -ATPase, a transmembrane protein essential for maintaining the electrochemical gradient across the plasma membrane, acts as a receptor for cardiotonic steroids such as ouabain. Cardiotonic steroids binding to Na /K -ATPase triggers signalling pathways or inhibits Na /K -ATPas activity in a concentration-dependent manner, resulting in a modulation of Ca levels, which are essential for homeostasis in neurons. However, most of the pharmacological strategies for avoiding neuronal death do not target Na /K -ATPase activity due to its complexity and the poor understanding of the mechanisms involved in Na /K -ATPase modulation. The present review aims to discuss two points regarding the interplay between Na /K -ATPase and Ca signalling in the brain. One, Na /K -ATPase impairment causing illness and neuronal death due to Ca signalling and two, benefits to the brain by modulating Na /K -ATPase activity. These interactions play an essential role in neuronal cell fate determination and are relevant to find new targets for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1111/bph.15419DOI Listing
February 2021

The role of Na+/K+-ATPase during chick skeletal myogenesis.

PLoS One 2015 16;10(3):e0120940. Epub 2015 Mar 16.

Laboratório de Diferenciação Muscular e Citoesqueleto, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

The formation of a vertebrate skeletal muscle fiber involves a series of sequential and interdependent events that occurs during embryogenesis. One of these events is myoblast fusion which has been widely studied, yet not completely understood. It was previously shown that during myoblast fusion there is an increase in the expression of Na+/K+-ATPase. This fact prompted us to search for a role of the enzyme during chick in vitro skeletal myogenesis. Chick myogenic cells were treated with the Na+/K+-ATPase inhibitor ouabain in four different concentrations (0.01-10 μM) and analyzed. Our results show that 0.01, 0.1 and 1 μM ouabain did not induce changes in cell viability, whereas 10 μM induced a 45% decrease. We also observed a reduction in the number and thickness of multinucleated myotubes and a decrease in the number of myoblasts after 10 μM ouabain treatment. We tested the involvement of MEK-ERK and p38 signaling pathways in the ouabain-induced effects during myogenesis, since both pathways have been associated with Na+/K+-ATPase. The MEK-ERK inhibitor U0126 alone did not alter cell viability and did not change ouabain effect. The p38 inhibitor SB202190 alone or together with 10 μM ouabain did not alter cell viability. Our results show that the 10 μM ouabain effects in myofiber formation do not involve the MEK-ERK or the p38 signaling pathways, and therefore are probably related to the pump activity function of the Na+/K+-ATPase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361648PMC
January 2016

Δ²,³-ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases.

Naunyn Schmiedebergs Arch Pharmacol 2011 Jan 19;383(1):101-7. Epub 2010 Nov 19.

Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Bloco J-sala 17, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Av. Carlos Chagas Filho 373, CEP: 21941-902, Rio de Janeiro, RJ, Brazil.

Looking at a new putative target for the large spectrum antiparasitic drug ivermectin, we recently showed that avermectin-derived drugs are active against promastigote and amastigote forms of Leishmania amazonensis at low micromolar concentrations. However, we then reported that at this concentration range ivermectin is also able to inhibit three important mammalian P-type ATPases so that unacceptable adverse effects could occur if this drug were used at such high doses therapeutically. The present work aimed to test the activity of ten ivermectin analogs on these rat ATPases in search of a compound with similar leishmanicidal activity but with no effect on the mammalian (host) ATPases at effective concentrations. We synthesized three new ivermectin analogs for testing on rat SERCA (1a and 1b), Na+, K+-ATPase (α₁ and α₂/α₃ isoforms) and H+/K+-ATPase activity, along with seven analogs already characterized for their leishmanicidal activity. Our main finding is that one of the prepared derivatives, Δ²,³-ivermectin ethyl secoester 8, is equipotent to ivermectin 1 for the in vitro leishmanicidal effects but is nearly without effect on the rat ATPases, indicating that it could have a better therapeutic index in vivo and could serve as a candidate for hit-to-lead progression. This conclusion is further supported by the fact that compound 8 produced only 6% (vs 77% for ivermectin) inhibition of the human kidney enzyme at 5 μM, a concentration corresponding to the IC₅₀ for the activity against L. amazonensis amastigotes.
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http://dx.doi.org/10.1007/s00210-010-0578-6DOI Listing
January 2011