Publications by authors named "Elisa Mitiko Kawamoto"

28 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

Inverse sex-based expression profiles of PTEN and Klotho in mice.

Sci Rep 2020 11 19;10(1):20189. Epub 2020 Nov 19.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences 1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, São Paulo, 05508-000, Brazil.

Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Taken together, our findings indicate that inverse sex-based regulation may be one of the underlying balancing mechanisms that differ between the sexes and a possible cause of sex-based autophagic and apoptotic responses to triggering situations that can lead to a sex-based predisposition to some neurological diseases.
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http://dx.doi.org/10.1038/s41598-020-77217-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677532PMC
November 2020

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies.

Front Nutr 2020 28;7:94. Epub 2020 Jul 28.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

The aging process is characterized by a series of molecular and cellular changes over the years that could culminate in the deterioration of physiological parameters important to keeping an organism alive and healthy. Physical exercise, defined as planned, structured and repetitive physical activity, has been an important force to alter physiology and brain development during the process of human beings' evolution. Among several aspects of aging, the aim of this review is to discuss the balance between two vital cellular processes such as autophagy and apoptosis, based on the fact that physical exercise as a non-pharmacological strategy seems to rescue the imbalance between autophagy and apoptosis during aging. Therefore, the effects of different types or modalities of physical exercise in humans and animals, and the benefits of each of them on aging, will be discussed as a possible preventive strategy against neuronal death.
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http://dx.doi.org/10.3389/fnut.2020.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399146PMC
July 2020

Insulin and Autophagy in Neurodegeneration.

Front Neurosci 2019 22;13:491. Epub 2019 May 22.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Crosstalk in the pathophysiological processes underpinning metabolic diseases and neurodegenerative disorders have been the subject of extensive investigation, in which insulin signaling and autophagy impairment demonstrate to be a common factor in both conditions. Although it is still somewhat conflicting, pharmacological and genetic strategies that regulate these pathways may be a promising approach for aggregate protein clearancing and consequently the delaying of onset or progression of the disease. However, as the response due to this modulation seems to be time-dependent, finding the right regulation of autophagy may be a potential target for drug development for neurodegenerative diseases. In this way, this review focuses on the role of insulin signaling/resistance and autophagy in some neurodegenerative diseases, discussing pharmacological and non-pharmacological interventions in these diseases.
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http://dx.doi.org/10.3389/fnins.2019.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558407PMC
May 2019

Ouabain increases neuronal branching in hippocampus and improves spatial memory.

Neuropharmacology 2018 09 9;140:260-274. Epub 2018 Aug 9.

Department of Pharmacology, Institute of Biomedical Science I University of São Paulo, Room 338, Av. Prof. Lineu Prestes, 1524, ICB I, Cidade Universitária, 05508-900, São Paulo, SP. Brazil. Electronic address:

Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFᴋB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-β-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats. The results show intrahippocampal injection of OUA 10 nM to activate the Wnt/β-Catenin signaling pathway and to increase CREB/BDNF and NFᴋB levels. These effects contribute to important changes in the cellular microenvironment, resulting in enhanced levels of dendritic branching in hippocampal neurons, in association with an improvement in spatial reference memory and the inhibition of long-term memory extinction.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.008DOI Listing
September 2018

The relevance of α-KLOTHO to the central nervous system: Some key questions.

Ageing Res Rev 2017 Jul 18;36:137-148. Epub 2017 Mar 18.

School of Life, Health & Chemical Sciences, The Open University, Milton Keynes MK7 6AA, United Kingdom. Electronic address:

α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear.
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http://dx.doi.org/10.1016/j.arr.2017.03.003DOI Listing
July 2017

Cardiotonic Steroids as Modulators of Neuroinflammation.

Front Endocrinol (Lausanne) 2016 16;7:10. Epub 2016 Feb 16.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo , Brazil.

Cardiotonic steroids (CTS) are a class of specific ligands of the Na(+), K(+)- ATPase (NKA). NKA is a P-type ATPase that is ubiquitously expressed and although well known to be responsible for the maintenance of the cell electrochemical gradient through active transport, NKA can also act as a signal transducer in the presence of CTS. Inflammation, in addition to importantly driving organism defense and survival mechanisms, can also modulate NKA activity and memory formation, as well as being relevant to many chronic illnesses, neurodegenerative diseases, and mood disorders. The aim of the current review is to highlight the recent advances as to the role of CTS and NKA in inflammatory process, with a particular focus in the central nervous system.
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http://dx.doi.org/10.3389/fendo.2016.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754428PMC
February 2016

The Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions.

Front Endocrinol (Lausanne) 2016 4;7. Epub 2016 Feb 4.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo , Brazil.

Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain. The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role in neurodegenerative processes, including in disorders such as in Alzheimer's and Parkinson's diseases. Sex hormones have also been shown to modulate cognitive functioning. Inflammation is a common feature in neurodegenerative disorders, and sex hormones/glucocorticoids can act to regulate inflammatory processes. Intermittent fasting can protect the brain against cognitive decline that is induced by an inflammatory stimulus. On the other hand, obesity increases susceptibility to inflammation, while metabolic syndromes, such as diabetes, are associated with neurodegeneration. Consequently, given that gonadal and/or adrenal steroids may significantly impact the pathophysiology of neurodegeneration, via their effect on inflammatory processes, this review focuses on how environmental factors, such as calorie intake and intermittent fasting, acting through their modulation of steroid hormones, impact on inflammation that contributes to cognitive and neurodegenerative processes.
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http://dx.doi.org/10.3389/fendo.2016.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740355PMC
February 2016

Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus.

Aging (Albany NY) 2015 Dec;7(12):1094-111

Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil.

Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-кB, as well as an increase in cytokines. Interestingly, both NF-кB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3β) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/β-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-кB activation, TNF-α and GCs increased levels, a decrease in AKT activation and an increase in GSK-3β activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/β-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712335PMC
http://dx.doi.org/10.18632/aging.100853DOI Listing
December 2015

Longevity Pathways (mTOR, SIRT, Insulin/IGF-1) as Key Modulatory Targets on Aging and Neurodegeneration.

Curr Top Med Chem 2015 ;15(21):2116-38

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Avenida Professor Lineu Prestes, 1524, São Paulo, Brazil, 05508-900.

Recent data from epidemiologic studies have shown that the majority of the public health costs are related to age-related disorders, and most of these diseases can lead to neuronal death. The specific signaling mechanisms underpinning neurodegeneration and aging are incompletely understood. Much work has been directed to the search for the etiology of neurodegeneration and aging and to new therapeutic strategies, including not only drugs but also non-pharmacological approaches, such as physical exercise and low-calorie dietary intake. The most important processes in aging-associated conditions, including neurodegeneration, include the mammalian (or mechanistic target of rapamycin (mTOR, sirtuin (SIRT and insulin/insulin growth factor 1 signaling (IIS pathways. These longevity pathways are involved in an array of different processes, including metabolism, cognition, stress response and brain plasticity. In this review we focus on the current advances involving the mTOR, SIRT and IIS longevity pathways during the course of healthy aging processes and neurodegenerative diseases, bringing new insights in the form of a better understanding of the signaling mechanisms underpinning neurodegeneration and how these differ from physiological normal aging processes. This also provides new targets for the therapeutic management and/or prevention of these devastating age-related disorders.
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http://dx.doi.org/10.2174/1568026615666150610125715DOI Listing
May 2016

Altered KLOTHO and NF-κB-TNF-α Signaling Are Correlated with Nephrectomy-Induced Cognitive Impairment in Rats.

PLoS One 2015 11;10(5):e0125271. Epub 2015 May 11.

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

Renal insufficiency can have a negative impact on cognitive function. Neuroinflammation and changes in klotho levels associate with chronic kidney disease (CKD) and may play a role in the development of cognitive impairment (CI). The present study evaluates the correlation of cognitive deficits with neuroinflammation and soluble KLOTHO in the cerebral spinal fluid (CSF) and brain tissue of nephrectomized rats (Nx), with 5/6 renal mass ablation. Nx and sham Munich Wistar rats were tested over 4 months for locomotor activity, as well as inhibitory avoidance or novel object recognition, which started 30 days after the surgery. EMSA for Nuclear factor-κB and MILLIPLEXMAP or ELISA kit were used to evaluate cytokines, glucocorticoid and KLOTHO levels. Nx animals that showed a loss in aversive-related memory and attention were included in the CI group (Nx-CI) (n=14) and compared to animals with intact learning (Nx-M n=12 and Sham n=20 groups). CSF and tissue samples were collected 24 hours after the last behavioral test. The results show that the Nx-groups have increased NF-κB binding activity and tumor necrosis factor-alpha (TNF-α) levels in the hippocampus and frontal cortex, with these changes more pronounced in the Nx-CI group frontal cortex. In addition, the Nx-CI group showed significantly increased CSF glucocorticoid levels and TNF-α /IL-10 ratio compared to the Sham group. Klotho levels were decreased in Nx-CI frontal cortex but not in hippocampus, when compared to Nx-M and Sham groups. Overall, these results suggest that neuroinflammation mediated by frontal cortex NF-κB, TNF-α and KLOTHO signaling may contribute to Nx-induced CI in rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427267PMC
February 2016

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus.

Neurobiol Aging 2015 May 28;36(5):1914-23. Epub 2015 Feb 28.

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

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.02.020DOI Listing
May 2015

Signaling function of Na,K-ATPase induced by ouabain against LPS as an inflammation model in hippocampus.

J Neuroinflammation 2014 Dec 31;11:218. Epub 2014 Dec 31.

Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, 05508-900, São Paulo, Brazil.

Background: Ouabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects. Lipopolysaccharide (LPS), via toll-like receptor 4 activation, is a widely used model to induce systemic inflammation. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats.

Methods: Adult male Wistar rats received acute intraperitoneal (ip) OUA (1.8 μg/kg) or saline 20 minutes before LPS (200 μg/kg, ip) or saline injection. Some of the animals had their femoral artery catheterized in order to assess arterial blood pressure values before and after OUA administration. Na,K-ATPase activity, cytokine mRNA levels, apoptosis-related proteins, NF-κB activation brain-derived neurotrophic factor BDNF, corticosterone and TNF-α levels were measured.

Results: OUA pretreatment decreased mRNA levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and IL-1β, which are activated by LPS in the hippocampus, but with no effect on serum measures of these factors. None of these OUA effects were linked to Na,K-ATPase activity. The involvement of the inflammatory transcription factor NF-κB in the OUA effect was indicated by its prevention of LPS-induced nuclear translocation of the NF-κB subunit, RELA (p65), as well as the decreased cytosol levels of the NF-κB inhibitor, IKB, in the hippocampus. OUA pretreatment reversed the LPS-induced glial fibrillary acidic protein (GFAP) activation and associated inflammation in the dentate gyrus. OUA also prevented LPS-induced increases in the hippocampal Bax/Bcl2 ratio suggesting an anti-apoptotic action in the brain.

Conclusion: Our results suggest that a low dose of OUA has an important anti-inflammatory effect in the rat hippocampus. This effect was associated with decreased GFAP induction by LPS in the dentate gyrus, a brain area linked to adult neurogenesis.
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http://dx.doi.org/10.1186/s12974-014-0218-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307894PMC
December 2014

Physiology and pathology of calcium signaling in the brain.

Front Pharmacol 2012 13;3:61. Epub 2012 Apr 13.

Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program Baltimore, MD, USA.

Calcium (Ca(2+)) plays fundamental and diversified roles in neuronal plasticity. As second messenger of many signaling pathways, Ca(2+) as been shown to regulate neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission, and other processes underlying learning and memory and cell survival. The flexibility of Ca(2+) signaling is achieved by modifying cytosolic Ca(2+) concentrations via regulated opening of plasma membrane and subcellular Ca(2+) sensitive channels. The spatiotemporal patterns of intracellular Ca(2+) signals, and the ultimate cellular biological outcome, are also dependent upon termination mechanism, such as Ca(2+) buffering, extracellular extrusion, and intra-organelle sequestration. Because of the central role played by Ca(2+) in neuronal physiology, it is not surprising that even modest impairments of Ca(2+) homeostasis result in profound functional alterations. Despite their heterogeneous etiology neurodegenerative disorders, as well as the healthy aging process, are all characterized by disruption of Ca(2+) homeostasis and signaling. In this review we provide an overview of the main types of neuronal Ca(2+) channels and their role in neuronal plasticity. We will also discuss the participation of Ca(2+) signaling in neuronal aging and degeneration.
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http://dx.doi.org/10.3389/fphar.2012.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325487PMC
October 2012

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system.

Age (Dordr) 2013 Apr 26;35(2):331-42. Epub 2012 Jan 26.

Department of Pharmacology, Institute of Biomedical Science-ICB-1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, 05508-900, São Paulo, Brazil.

Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study age-related disorders and new anti-aging therapies.
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http://dx.doi.org/10.1007/s11357-011-9365-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592952PMC
April 2013

The role of Wnt signaling and its interaction with diverse mechanisms of cellular apoptosis in the pathophysiology of bipolar disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2011 Jan 7;35(1):11-7. Epub 2010 Sep 7.

Bipolar Disorder Research Program, Department of Psychiatry, Medical School, University of São Paulo, São Paulo, Brazil.

The neurobiology of Bipolar Disorder (BD) is not completely understood, although abnormalities in neuroplasticity and control of apoptosis have been considered as central events in its pathophysiology. The molecules of the Wnt family comprise a class of proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation with their actions largely exerted by modulating gene transcription. The Wnt signaling pathway has interface with some mediators with a well documented action in neuroplasticity and regulation of cell surviving. In addition, mood stabilizers such as lithium and valproate may have their neuroprotective properties in part mediated by the Wnt pathway. This article is an overview of how the Wnt signaling cascade might be involved in the pathogenesis of BD and also in details of intracellular events related to this pathway. Further studies of Wnt signaling may lead to a better comprehension of the neuroprotective actions of mood stabilizers and contribute to improving the therapeutics of BD.
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http://dx.doi.org/10.1016/j.pnpbp.2010.08.031DOI Listing
January 2011

Peripheral biomarkers of oxidative stress in aging and Alzheimer's disease.

Dement Neuropsychol 2008 Jan-Mar;2(1):2-8

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

Aging is associated with a greatly increased incidence of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). These conditions are associated with chronic inflammation, which generates oxygen reactive species, ultimately responsible for a process known as oxidative stress. It is well established that this process is the culprit of neurodegeneration, and there are also mounting evidences that it is not restricted to the central nervous system. Indeed, several studies, including some by our group, have demonstrated that increased peripheral oxidative stress markers are associated to aging and, more specifically, to AD. Therefore, it is very instigating to regard aging and AD as systemic conditions that might be determined by studying peripheral markers of oxidative stress.
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http://dx.doi.org/10.1590/S1980-57642009DN20100002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619146PMC
December 2017

Age-related changes in cerebellar phosphatase-1 reduce Na,K-ATPase activity.

Neurobiol Aging 2008 Nov 29;29(11):1712-20. Epub 2007 May 29.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Avenida Lineu Prestes, 1524, 05508-900 São Paulo, Brazil.

We evaluated whether changes in protein content and activity of PP-1 and PP-2A were the mechanism underneath the basal age-related reduction in alpha(2/3)-Na,K-ATPase activity in rats cerebella and whether this occurred through the cyclic GMP-PKG pathway. PP1 activity, but not its expression, increased with age, whereas PP-2 was not changed. The activity of alpha(2/3)-Na,K-ATPase varied with age, and there was a negative association between the PP-1 and alpha(2/3)-Na,K-ATPase activities. In young rats, the inhibition of PP-1 and PP-2A by okadaic acid (OA) increased in a dose-dependent manner alpha(1)- and alpha(2/3)-Na,K-ATPase, but had no effect on Mg-ATPase activity. A direct stimulation of PKG with 8-Br-cyclic GMP did not surmount the effect of OA. This analogue of cyclic GMP inhibited PP-1 activity only, indicating that at least part of the increase in alpha(1)- and alpha(2/3)-Na,K-ATPase activity induced by OA was mediated by the cyclic GMP-PKG-PP-1 cascade. Taking into account that PP1 inhibition increased alpha(2/3)-Na,K-ATPase activity, we propose that an age-related increase in PP-1 activity due to a decrease in cyclic GMP-PKG modulation plays a role for the age-related reduction of alpha(2/3)-Na,K-ATPase activity in rat cerebellum.
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http://dx.doi.org/10.1016/j.neurobiolaging.2007.04.008DOI Listing
November 2008

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation.

Br J Pharmacol 2006 Jul 15;148(5):629-39. Epub 2006 May 15.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, ICB, University of São Paulo, Av. Professor Lineu Prestes, 1524, sala 101B, 05508-900 São Paulo, SP, Brazil.

1. The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg-1 day-1, s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2. Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of Nomega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 microM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3. Neither losartan (10 microM) nor indomethacin (10 microM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml-1) and L-arginine (5 mM), but neither catalase (300 U ml-1) nor apocynin (100 microM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4. In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO-mediated negative modulation even in the presence of high NO production and antioxidant defence.
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http://dx.doi.org/10.1038/sj.bjp.0706749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751879PMC
July 2006

Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion.

J Neurosci 2006 Apr;26(14):3813-20

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, 05508-900, Brazil.

Although the anti-inflammatory actions of glucocorticoids (GCs) are well established in the periphery, these stress hormones can increase inflammation under some circumstances in the brain. The transcription factor nuclear factor-kappaB (NF-kappaB), which is inhibited by GCs, regulates numerous genes central to inflammation. In this study, the effects of stress, GCs, and NMDA receptors on lipopolysaccharide (LPS)-induced activation of NF-kappaB in the brain were investigated. One day after chronic unpredictable stress (CUS), nonstressed and CUS rats were treated with saline or LPS and killed 2 h later. CUS potentiated the increase in LPS-induced activation of NF-kappaB in frontal cortex and hippocampus but not in the hypothalamus. This stress effect was blocked by pretreatment of rats with RU-486, an antagonist of the GC receptor. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], an NMDA receptor antagonist, also reduced the effect of LPS in all three brain regions. However, the combined antagonism of both GC and NMDA receptors produced no further reduction in NF-kappaB activation when compared with the effect of each treatment alone. Our results indicate that stress, via GC secretion, can increase LPS-induced NF-kappaB activation in the frontal cortex and hippocampus, agreeing with a growing literature demonstrating proinflammatory effects of GCs.
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http://dx.doi.org/10.1523/JNEUROSCI.4398-05.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674142PMC
April 2006

Age-related changes in cyclic GMP and PKG-stimulated cerebellar Na,K-ATPase activity.

Neurobiol Aging 2005 Jun;26(6):907-16

Department of Pharmacology, Institute of Biomedical Science University of São Paulo Avenida Lineu Prestes, São Paulo 152405508-900, Brazil.

Energy deficiency and dysfunction of the Na,K-ATPase are common consequences of many pathological insults. Glutamate through cyclic GMP and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate alpha(2/3)-Na,K-ATPase activity in the central nervous system. Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. We investigate the effect of aging (4, 12 and 24 months) on the glutamate-cyclic GMP-PKG modulation of alpha1, alpha(2/3)-Na,K-ATPase activity in rat cerebellum and the stimulation of the glutamate-cyclic GMP-PKG pathway at different levels. Cyclic GMP levels and alpha(2/3)-Na,K-ATPase activity were progressively decreased from 4 and 24 month-old animals. However, PKG basal activity was reduced between 4 and 12 months, and no additional change was observed at 24 months. The ability of 8-Br-cyclic GMP to stimulate PKG activity was only reduced between 12 and 24 months. Moreover, glutamate or 8-Br-cyclic GMP promoted a smaller increase of alpha(2/3)-Na,K-ATPase activity at 24 months, when compared to 4 and 12 months. In spite of the age-related reduced basal levels of cyclic GMP, the production induced by CO or NO was not age-related. Finally, inhibition of PKG activation by KT5823 revealed a lower sensitivity of the enzyme at the older age. Taken together, these data show that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate positive modulation of cerebellar alpha(2/3)-Na,K-ATPase is linked to a defective PKG signaling pathway.
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http://dx.doi.org/10.1016/j.neurobiolaging.2004.08.013DOI Listing
June 2005

Oxidative state in platelets and erythrocytes in aging and Alzheimer's disease.

Neurobiol Aging 2005 Jun;26(6):857-64

Department of Pharmacology, School of Medicine, University of São Paulo, São Paulo, Brazil.

Several studies have shown involvement of peroxynitrite anion, a potent oxidative agent, in Alzheimer's disease (AD) neuropathology. Herein, we assessed in platelets and erythrocytes of AD patients, age-matched and young adults controls: thiobarbituric acid-reactive substances (TBARS) production; superoxide dismutase (SOD), nitric oxide synthase (NOS) and Na,K-ATPase activities; cyclic GMP (cGMP) content, both basal and after sodium nitroprusside (SNP) stimulation. Aging was associated with an increase in TBARS production and NOS activity, a decrease in basal cGMP content and no change in SOD and Na,K-ATPase activities. AD patients, compared to aged controls, have: increase in TBARS production and in NOS, SOD and Na,K-ATPase activities but no alteration in basal cGMP content. SNP increased cGMP platelets production in all groups. In conclusion, we demonstrated in platelets and erythrocytes a disruption in systemic modulation of oxidative stress in aging and with more intensity in AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2004.08.011DOI Listing
June 2005

Glutamate modulates sodium-potassium-ATPase through cyclic GMP and cyclic GMP-dependent protein kinase in rat striatum.

Cell Biochem Funct 2005 Mar-Apr;23(2):115-23

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

Excessive excitatory action of glutamate and nitric oxide (NO) has been implicated in degeneration of striatal neurons. Evidence had been provided that Na+K+-ATPase might be involved in this process. Here we investigated whether glutamate-regulated messengers, such as NO and cyclic GMP, could modulate the activity of membrane Na+K+-ATPase. Our results demonstrated that NO donors sodium nitroprusside (SNP at 30 and 300 microM) and S-nitroso-N-acetylpenicillamine (SNAP at 200 microM) increased alpha2,3Na+K+-ATPase activity which was blocked by the NO chelator, haemoglobin and was independent of [Na+]. This regulation was associated with cGMP synthesis and mimicked by glutamate (300 microM) and 8-Br-cyclic GMP (4 mM). 8-Br-cGMP-induced stimulation of Na+K+-ATPase activity could be blocked by KT5823 (an inhibitor of cGMP-dependent protein kinase, PKG), but not by KT5720 (an inhibitor of cAMP-dependent protein kinase, PKA). N-Methyl-D-aspartate (NMDA) receptors appeared to be involved in the effect of glutamate, since MK-801 (NMDA receptor antagonist) produced a partial reduction in glutamate-induced activation of the enzyme. MK-801 was not synergistic to L-NAME (NOS inhibitor), suggesting that glutamate stimulates the NMDA-NOS pathway to activate alpha2,3 Na+K+-ATPase in rat striatum. This regulation was associated with cyclic GMP (but not cyclic AMP) synthesis. These data indicate the existence, in vitro, of a regulatory pathway by which glutamate, acting through NO and cGMP, can cause alterations in striatal alpha2,3 Na+K+-ATPase activity.
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http://dx.doi.org/10.1002/cbf.1217DOI Listing
June 2005

Changes in sodium, potassium-ATPase induced by repeated fencamfamine: the roles of cyclic AMP-dependent protein kinase and the nitric oxide-cyclic GMP pathway.

Neuropharmacology 2003 Dec;45(8):1151-9

Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Avenida Prof Lineu Prestes, 1524 Cidade Universitária, São Paulo 05508-900, SP, Brazil.

Fencamfamine (FCF) is an indirect dopamine agent with effects similar to amphetamine and cocaine. In the present study, we investigate changes in Na,K-ATPase, cyclic AMP-dependent protein kinase (PKA) and nitric oxide synthase (NOS) activity and cyclic GMP levels in the nucleus accumbens (NAc) and striatum (ST) of animals acutely or repeatedly treated with FCF (3.5 mg/kg). Na,K-ATPase had a similar activity in control and repeatedly treated animals, but was reduced in the NAc of the acute group. This enzyme was reduced in the ST in acute and repeatedly treated animals, compared to the control group. Expression of the alpha(1,2,3)-Na,K-ATPase isoforms in the NAc and the ST was not altered in all groups studied. Acute FCF induced a significant increase in PKA activity in both the ST and the NAc. Repeatedly treated animals showed a higher increase in PKA activity in the NAc, but not in the ST, when compared to the acute group. There was also an increase in both NOS activity and cyclic GMP levels only in the NAc of FCF repeatedly treated animals compared to the acute and control groups. We suggest that chronic FCF treatment is linked to a modification in Na,K-ATPase activity through the PKA and NO-cyclic GMP pathway.
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http://dx.doi.org/10.1016/s0028-3908(03)00278-8DOI Listing
December 2003

MK-801 and 7-Ni attenuate the activation of brain NF-kappa B induced by LPS.

Neuropharmacology 2003 Dec;45(8):1120-9

Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science-ICB-1, Avenida Professor Lineu Prestes, 1524, University of São Paulo, Sao Paulo 05508-900, Brazil.

The activation of nuclear factor-kappaB (NF-kappaB) leads to an increase in the expression of genes involved in important events in the central nervous system (CNS), such as development, plasticity and inflammation. It has been shown that inflammatory stimulus in the brain increases excitatory glutamatergic transmission, especially at N-methyl-D-aspartate (NMDA) receptor. These receptors have an important role in glutamate neurotoxicity and are in general coupled with the generation of nitric oxide (NO) through the activation of neuronal nitric oxide synthase (NOS). We have investigated the involvement of NMDA-NO pathway in LPS induction of NF-kappaB in CNS. Our results demonstrate that systemic LPS activates NF-kappaB in several regions of the CNS, which was partially reduced by the NMDA receptor antagonist dizolcipine (MK-801) and by the selective brain NOS inhibitor 7-Nitroindazol (7-Ni). 7-Ni effects were not synergic to MK-801 effects, suggesting that these compounds act through the same pathway. Dexamethasone caused a stronger reduction in LPS induction of NF-kappaB in CNS, demonstrating that MK-801 and 7-Ni act on a pathway that is responsible only by a fraction of the overall NF-kappaB activation. These results suggest that a considerable part of NF-kappaB activation by LPS is linked to the NMDA/NO pathway in CNS.
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http://dx.doi.org/10.1016/s0028-3908(03)00279-xDOI Listing
December 2003

Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero.

J Cardiovasc Pharmacol 2002 Oct;40(4):501-9

Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, SP, Brazil.

Maternal undernutrition during critical periods of organ development is known to impair fetal growth and predispose to the development of adulthood diseases, such as hypertension, coronary heart disease and type II diabetes that are linked to low birth weight and are characterized by endothelial dysfunction. Increased oxidative stress, in rats submitted to intrauterine undernutrition, provides a potential explanation for the endothelial dysfunction development. The aim of this study was to determine the oxidative stress and its consequence on mesenteric arteriolar responses to vasoactive agents in offspring from diet-restricted dams. For this, female pregnant Wistar rats were fed either normal or 50% of normal intake diets, during the whole gestational period. In male offspring, arterial blood pressure was determined by the tail cuff method in anesthetized rats, mesenteric arteriolar reactivity and superoxide anion generation were studied using intravital microscopy and superoxide dismutase activity was determined in mesentery by spectrophotometric assay. Intrauterine undernutrition induced hypertension, decreased vasodilation to acetylcholine and bradykinin but did not alter the responses to sodium nitroprusside. Topical application of superoxide dismutase and superoxide dismutase mimetic manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin significantly improved the altered arteriolar responses to acetylcholine and bradykinin. A decreased superoxide dismutase activity and an increased superoxide anion concentration were observed in the offspring of diet-restricted dams. This study shows for the first time that intrauterine undernutrition enhances oxidative stress in vivo and relates this to the impaired endothelium-dependent vasodilation.
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http://dx.doi.org/10.1097/00005344-200210000-00002DOI Listing
October 2002

Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring.

Cardiovasc Res 2002 Oct;56(1):145-53

Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Av. Prof Lineu Prestes, 1524- São Paulo, SP, Brazil.

Objective: Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension in adulthood. In an attempt to define the mechanisms whereby blood pressure may be raised, we have hypothesized that arteries from offspring of nutritionally restricted dams exhibit abnormalities in the endothelial function and in nitric oxide synthesis. In order to investigate the existence of potential gender differences on the effects of intrauterine undernutrition, both male and female offspring of pregnant Wistar rats on normal and restricted diets were studied in adulthood.

Methods: Female pregnant Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. At 14 weeks of age, the rats were used for the study of vascular reactivity, eNOS and iNOS gene expression, eNOS activity and, in the case of females, estrogen levels.

Results: Intrauterine undernutrition induced hypertension in both male and female offspring, but hypertension was more severe in male rats. Endothelium-intact aortic rings from male and female rats in the restricted diet group exhibited increased responses to norepinephrine, decreased vasodilation to acetylcholine and unaltered responses to sodium nitroprusside in comparison to aortic rings from control rats. No gender-related differences were observed in the vascular reactivity studies. Intrauterine undernutrition promoted decreased gene expression for eNOS in aorta isolated from male, but not female, offspring, reduction in eNOS activity in both male and female offspring and impairment in synthesis of estrogen in female offspring.

Conclusion: Our data show that intrauterine undernutrition: (1) induces hypertension both in the male and female offspring, hypertension being more severe in male than in female rats; (2) alters endothelium-dependent responses in aortas from the resulting offspring. The endothelial dysfunction is associated with a decrease in activity/expression of eNOS in aortas from male offspring. The mechanism involved in altered response to ACh in female offspring might be a consequence of reduction in estrogen levels leading to reduced eNOS activity.
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http://dx.doi.org/10.1016/s0008-6363(02)00508-4DOI Listing
October 2002

Panic disorder patients have reduced cyclic AMP in platelets.

J Psychiatr Res 2002 Mar-Apr;36(2):105-10

Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.

Little is known about the intracellular mechanisms involved in the pathophysiology of panic disorder (PD). Abnormalities in the cyclic AMP system have been described in several psychiatric disorders but there are no studies in panic patients. We evaluated not only the levels of platelet cyclic AMP, but also cyclic GMP and nitric oxide synthase (NOS) activity in patients with PD at baseline and after treatment with clomipramine and in healthy volunteers. Platelet cyclic AMP was determined by enzymeimmunoassay, cyclic GMP by radioimmunoassay and NOS activity by the conversion of (3)H-arginine to (3)H-citruline in 17 PD patients before treatment with clomipramine, after remission of panic attacks and in 22 healthy volunteers. Average baseline cyclic AMP of PD patients was lower than after remission of panic attacks (P<0.005) and lower than in healthy volunteers (P<0.005). Average cyclic AMP after remission of panic attacks was not significantly different than in healthy volunteers. There were no significant differences in cyclic GMP and NOS analysis. Our results suggest that PD patients without treatment have lower platelets cyclic AMP levels than healthy volunteers and that this decrease may be corrected by clomipramine.
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http://dx.doi.org/10.1016/s0022-3956(01)00053-xDOI Listing
May 2002