Nuestros investigadores

Maite Solas Zubiaurre

Departamento
Farmacología y Toxicología
Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Enfermedad de Alzheimer, Estudio de los factores de riesgo ambientales de la Enfermedad de Alzheimer y búsqueda de nuevos tratamientos farmacológicos preventivos o curativos para dicha enfermedad
Índice H
7, (Google Scholar, 03/03/2014)

Publicaciones científicas más recientes (desde 2010)

Autores: Vela, S.; Sáinz, Neira; Moreno-Aliaga MJ; et al.
Revista: MOLECULAR NEUROBIOLOGY
ISSN 0893-7648  Vol. 56  Nº 3  2019  págs. 1618 - 1627
A potential role of marine n-3 polyunsaturated fatty acids (-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, -3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of -3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
Autores: Solas, Maite; Cuadrado-Tejedor M.; et al.
Revista: ACTA PHYSIOLOGICA
ISSN 1748-1708  Vol. 227  Nº Supl. 718  2019  págs. 83 - 84
Autores: Solas, Maite; Pejenaute, Álvaro; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 139  Nº S1  2019  págs. S17 - S17
Autores: Ramírez, M.J.; Milagro FI; et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 10  Nº 10  2018 
Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
Autores: Moreno, L. C. G. E. A. I.; Solas, Maite; Martínez-Oharriz, M.C.; et al.
Revista: INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN 0378-5173  Vol. 543  Nº 1 - 2  2018  págs. 245 - 256
Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 mu g/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.
Autores: Solas, Maite; et al.
Revista: MOLECULAR NEUROBIOLOGY
ISSN 0893-7648  Vol. 55  Nº 12  2018  págs. 9328 - 9333
Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total III-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.
Autores: Larrayoz, I. M.; Martisová, Eva; et al.
Revista: MOLECULAR NEUROBIOLOGY
ISSN 0893-7648  Vol. 55  Nº 6  2018  págs. 5177 - 5183
Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
Autores: Solas, Maite; Milagro FI; Ramírez, M.J.; et al.
Revista: CURRENT OPINION IN PHARMACOLOGY
ISSN 1471-4892  Vol. 37  2017  págs. 87 - 92
Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed 'gut-brain axis'. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.
Autores: Ferrero, H.; Solas, Maite; Francis, P. T.; et al.
Revista: CNS DRUGS
ISSN 1172-7047  Vol. 31  Nº 1  2017  págs. 19 - 32
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6 receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
Autores: Lopez, V.; Nielsen, B. ; Solas, Maite; et al.
Revista: FRONTIERS IN PHARMACOLOGY
ISSN 1663-9812  Vol. 8  2017  págs. 280
Lavender essential oil is traditionally used and approved by the European Medicines Agency (EMA) as herbal medicine to relieve stress and anxiety. Some animal and clinical studies reveal positive results in models of anxiety and depression although very little research has been done on molecular mechanisms. Our work consisted of evaluating the effects of lavender (Lavandula angustifolia) essential oil on central nervous system well-established targets, such as MAO-A, SERT, GABA(A)and NMDA receptors as well as in vitro models of neurotoxicity. The results showed that lavender essential oil and its main components exert affinity for the glutamate NMDA-receptor in a dose-dependent manner with an IC50 value of 0.04 mu l/mL for lavender oil. In addition, lavender and linalool were also able to bind the serotonin transporter (SERT) whereas they did not show affinity for GABA(A)-benzodiazepine receptor. In three different models of neurotoxicity, lavender did not enhance the neurotoxic insult and improved viability of SH-SY5Y cells treated with hydrogen peroxide. According to our data, the anxiolytic and antidepressant-like effects attributed to lavender may be due to an antagonism on the NMDA-receptor and inhibition of SERT. This study suggests that lavender essential oil may exert pharmacological properties via modulating the NMDA receptor, the SERT as well as neurotoxicity induced by hydrogen peroxide.
Autores: Ferrero, H.; Solas, Maite; Francis, P. T.; et al.
Revista: CNS DRUGS
ISSN 1172-7047  Vol. 31  Nº 1  2017  págs. 19 - 32
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been furt(h)er developed into ongoing phase III clinical trials. Overall, 5-HT6 receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
Autores: Yarza, R.; Solas, Maite; et al.
Revista: FRONTIERS IN PHARMACOLOGY
ISSN 1663-9812  Vol. 6  2016  págs. 321
c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death, and regulation of cellular senescence. It has been shown that there is a JNK pathway activation after exposure to different stressing factors, including cytokines, growth factors, oxidative stress, unfolded protein response signals or 4 peptides. Altogether, JNKs have become a focus of screening strategies searching for new therapeutic approaches to diabetes, cancer or liver diseases. In addition, activation of JNK has been identified as a key element responsible for the regulation of apoptosis signals and therefore, it is critical for pathological cell death associated with neurodegenerative diseases and, among them, with Alzheimer's disease (AD). In addition, in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with pathogenesis and neuronal death in AD. JNK's, particularly JNK3, not only enhance 4 production, moreover it plays a key role in the maturation and development of neurofibrillary tangles. This review aims to explain the rationale behind testing therapies based on inhibition of JNK signaling for AD in terms of current knowledge about the pathophysiology of the disease. Keeping in mind that JNK3 is specifically expressed in the brain and activated by stress-stimuli, it is possible to hypothesize that inhibition of JNK3 might be considered as a potential target for treating neurodegenerative mechanisms associated with AD.
Autores: Solas, Maite; Milagro FI; Martínez, Diego; et al.
Revista: TRENDS IN PHARMACOLOGICAL SCIENCES
ISSN 0165-6147  Vol. 37  Nº 7  2016  págs. 575-593
Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management.
Autores: Solas, Maite; Ramírez, M.J.;
Revista: JOURNAL OF ALZHEIMERS DISEASE
ISSN 1387-2877  Vol. 50  Nº 4  2016  págs. 963 - 967
In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.
Autores: Solas, Maite; Moreno-Aliaga MJ; et al.
Revista: BIOCHIMICA ET BIOPHYSICA ACTA
ISSN 0006-3002  Vol. 1862  Nº 4  2016  págs. 511 - 517
The concept of central insulin resistance and dysfunctional insulin signalling in sporadic Alzheimer's disease (AD) is now widely accepted and diabetes is recognized as one of the main risk factors for developing AD. Moreover, some lines of evidence indicated that VGlut1 is impaired in frontal regions of AD patients and this impairment is correlated with the progression of cognitive decline in AD. The present work hypothesizes that ketosis associated to insulin resistance could interfere with the normal activity of VGlut1 and its role in the release of glutamate in the hippocampus, which might ultimately lead to cognitive deficits. High fat diet (HFD) rats showed memory impairments and both peripheral (as shown by increased fasting plasma insulin levels and HOMA index) and hippocampal (as shown by decreased activation of insulin receptor, IRS-1 and pAkt) insulin pathway alterations, accompanied by increased ketone bodies production. All these effects were counteracted by ¿-lipoic acid (LA) administration. VGlut1 levels were significantly decreased in the hippocampus of HFD rats, and this decrease was reversed by LA. Altogether, the present results suggest that HFD induced alterations in central insulin signalling could switch metabolism to produce ketone bodies, which in turn, in the hippocampus, might lead to a decreased expression of VGlut1, and therefore to a decreased release of glutamate and hence, to the glutamatergic deficit described in AD. The ability of LA treatment to prevent the alterations in insulin signalling in this model of HFD might represent a possible new therapeutic target for the treatment of AD.
Autores: Tordera, R.M.; Gil, Francisco Javier; et al.
Revista: HIPPOCAMPUS
ISSN 1050-9631  Vol. 26  Nº 10  2016  págs. 1303 - 1312
Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and beta-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of A beta on glutamatergic terminals; therefore the aim of this study was to investigate how A beta affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that A beta caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when A beta was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when A beta(1-42) was intracerebroventricularlly administered into VGLUT1+/-mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to A beta induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels ...
Autores: Jais, A.; Solas, Maite; Backes, H.; et al.
Revista: CELL
ISSN 0092-8674  Vol. 165  Nº 4  2016  págs. 882 - 895
High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(¿myel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(¿myel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.
Autores: Solas, Maite; Puerta, Elena; Ramírez, M.J.;
Revista: CURRENT PHARMACEUTICAL DESIGN
ISSN 1381-6128  Vol. 21  Nº 34  2015  págs. 4960 - 4971
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit, but unfortunately, it has been only successful in terms of developing symptomatic treatments. Aß deposition and neurofibrillary tangles along with neuron and synapse loss are associated with neurotransmitter dysfunction and have been recognized as hallmarks of AD. Furthermore, clinical and preclinical studies point to this neurotransmitter dysfunction as a main factor underlying both cognitive and neuropsychiatric symptoms of the illness. Cholinergic deficit in AD prompted the use of cholinesterase inhibitors as the symptomatic treatment of cognitive decline in AD, however this therapeutic approach provides only modest benefit in the majority of patients. Hence, nowadays research is focused on investigating compounds that could restore cognition and memory in AD patients. GABA is the primary inhibitory neurotransmitter in the central nervous system and GABAergic neurons provide extensive innervation to cholinergic and glutamatergic neurons. It has been shown that dysfunction of the GABAergic system may contribute to cognitive impairment in humans. Significant reductions in GABA levels have been described in severe cases of AD, which could be underlying the behavioral and psychological symptoms of AD. This review examines the involvement of the GABAergic system in both cognitive and non-cognitive behavioural symptoms in AD, providing some pointers for rational drug development.
Autores: Steculorum, S.M.; Solas, Maite; Brüning, J. C.;
Revista: ALZHEIMERS AND DEMENTIA
ISSN 1552-5260  Vol. 10  Nº 1  2014  págs. S3 - S11
During past decades, ever-increasing life expectancy, despite the development of a sedentary lifestyle and altered eating habits, has led to a dramatic parallel increase in the prevalence of age-related diseases such as type 2 diabetes mellitus (T2DM) and neurodegenerative disorders. Converging evidence from animal and human studies has indicated that insulin resistance in the central nervous system (CNS) is observed in both T2DM and neurodegenerative disorders such as Alzheimer¿s disease (AD), leading to the hypothesis that impaired neuronal insulin action might be a unifying pathomechanism in the development of both diseases. This assumption, however, is in striking contrast to the evolutionary conserved, protective role of impaired insulin/insulin-like growth factor 1 signaling (IIS) in aging and in protein aggregation-associated diseases, such as AD. Thus, this review summarizes our current understanding of the physiological role of insulin action in various regions of the CNS to regulate neuronal function, learning, and memory, and to control peripheral metabolism. We also discuss mechanisms and clinical outcomes of neuronal insulin resistance and address the seeming paradox of how impaired neuronal IIS can protect from the development of neurodegenerative disorders.
Autores: Solas, Maite; Guereñu, Gorka; Gil, Francisco Javier; et al.
Revista: JOURNAL OF NEUROENDOCRINOLOGY
ISSN 0953-8194  Vol. 25  Nº 4  2013  págs. 350 - 356
It is becoming evident that chronic exposure to glucocorticoids might not only result in insulin resistance or cognitive deficits, but also is considered as a risk factor for pathologies such as depression or Alzheimer's disease. In the present study, in vivo experiments using a non-invasive method of chronic administration of corticosterone in drinking water demonstrated that chronic corticosterone administration led to cognitive impairment in the novel object recognition test and insulin resistance, as shown by significant increases in plasma insulin levels and the homeostatic model assessment index, and decreased insulin receptor phosphorylation. Corticosterone treatment induced an increased expression of stress-activated c-Jun N-terminal kinase (JNK) in the hippocampus, accompanied by decreases in glycogen synthase kinase 3, increases in pTau levels and increased neuronal cell death (caspase-3 activity). All these effects were reversed by the administration of a JNK1 inhibitor or by the mineralocorticoid receptor antagonist spironolactone. It is suggested that the mineralocorticoid receptors and JNK-mediated pathways are involved in the interaction of glucocorticoid-insulin resistance and the development of relevant cellular processes for Alzheimers disease
Autores: Solas, Maite; Aisa, Bárbara; Tordera, R.M.; et al.
Revista: BIOCHIMICA ET BIOPHYSICA ACTA
ISSN 0006-3002  Vol. 1832  Nº 12  2013  págs. 2332 - 2339
It is becoming evident that chronic exposure to stress not only might result in insulin resistance or cognitive deficits, but may also be considered a risk factor for pathologies such as depression or Alzheimer's disease (AD). There is great interest in determining the molecular mechanisms underlying interactions between stress, aging, memory and Alzheimer's disease (AD). We have used the chronic mild stress (CMS) model to study the effects of chronic stress on the aging process and the development of central insulin resistance and AD pathology. CMS aged mice showed cognitive impairments in the novel object recognition test. In addition, CMS aged mice displayed both peripheral insulin resistance, as shown by HOMA index, and decreased hippocampal levels of pIRS and downstream intracellular signaling (pAKT, pGSK and pERK1/2). Interestingly, there was a significant increase in both C99:C83 ratio and BACE1 levels in the hippocampus of CMS aged mice. Increased expression of the AD marker pTau was also found in stressed aged mice. Increased expression of the stress-activated protein kinase JNK was found in CMS aged mice, accompanied by significant decreases in glucocorticoid receptor (GR) expression and increases in mineralocorticoid receptor (MR) expression. It is suggested that the interaction of stress with aging should be considered when studying determinants of the onset and progression of AD.
Autores: Solas, Maite; Francis, Paul T; et al.
Revista: NEUROBIOLOGY OF AGING
ISSN 0197-4580  Vol. 34  Nº 3  2013  págs. 805-808
The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer's disease (AD). The relationship of cannabinoid receptors (CB1R and CB2R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB1R and CB2R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB1R expression was significantly decreased in AD. Levels of CB1R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB2R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB2R expression did not correlate with cognitive status. Interestingly, expression levels of CB2R correlated with two relevant AD molecular markers, A beta(42) levels and senile plaque score. These results may constitute the basis of CB2R-based therapies and/or diagnostic approaches. (C) 2013 Elsevier Inc. All rights reserved.
Autores: Briones, A; Gagno, S; Martisová, Eva; et al.
Revista: BRITISH JOURNAL OF PHARMACOLOGY
ISSN 0007-1188  Vol. 165  Nº 4  2012  págs. 897-907
Autores: Martisová, Eva; Solas, Maite; Guereñu, Gorka; et al.
Revista: CURRENT ALZHEIMER RESEARCH
ISSN 1567-2050  Vol. 9  Nº 7  2012  págs. 822 - 829
The objective of the present work was to study a purported involvement of stress in amyloid pathology through the modulation of BACE expression. Early-life stressed rats (maternal separation, MS) showed significant increases in corticosterone levels, BACE expression and Aß levels. The CpG7 site of the BACE promoter was significantly hypomethylated in MS, and corticosterone levels negatively correlated to the methylation status of CpG7. The activation of the stress-activated protein kinase JNK was also increased in MS rats. In SHSY-5Y neuroblastoma cells, corticosterone induced a rapid increase in BACE expression that was abolished by specific inhibiton of JNK activation or by spironolactone, a mineralocorticoid receptor antagonist, but not by mifepristone, a glucocorticoid receptor antagonist. Corticosterone was also able to increase pJNK expression and this effect was fully reverted by spironolactone. Mice chronically treated with corticosterone showed increased BACE and pJNK expression. These increases were reverted by treatment with spironolactone or with a JNK inhibitor. It is suggested that increased corticosterone levels associated to stress lead to increase BACE transcription both through epigenetic mechanisms and activation of JNK.
Autores: Martisová, Eva; Solas, Maite; Horrillo, I; et al.
Revista: NEUROPHARMACOLOGY
ISSN 0028-3908  Vol. 62  Nº 5-6  2012  págs. 1944 - 1953
The objective of the present work was to study the effects of an early-life stress (maternal separation, MS) in the excitatory/inhibitory ratio as a potential factor contributing to the ageing process, and the purported normalizing effects of chronic treatment with the antidepressant venlafaxine. MS induced depressive-like behaviour in the Porsolt forced swimming test that was reversed by venlafaxine, and that persisted until senescence. Aged MS rats showed a downregulation of vesicular glutamate transporter 1 and 2 (VGIut1 and VGIut2) and GABA transporter (VGAT) and increased expression of excitatory amino acid transporter 2 (EAAT2) in the hippocampus. Aged rats showed decreased expression of glutamic acid decarboxylase 65 (GAD65), while the excitatory amino acid transporter 1 (EAAT1) was affected only by stress. Glutamate receptor subunits NR1 and NR2A and GIuR4 were upregulated in stressed rats, and this effect was reversed by venlafaxine. NR2B, GluR1 and GluR2/3 were not affected by either stress or age. MS, both in young and aged rats, induced an increase in the circulating levels of corticosterone. Corticosterone induced an increase glutamate and a decrease in GABA release in hippocampal slices, which was reversed by venlafaxine. Chronic treatment with corticosterone recapitulated the main biochemical findings observed in MS. The different effects that chronic stress exerts in young and adult animals on expression of proteins responsible for glutamate/GABA cycling may explain the involvement of glucocorticoids in ageing-related diseases. Modulation of glutamate/GABA release may be a relevant component of the therapeutic action of antidepressants, such as venlafaxine.
Autores: Gil, Francisco Javier; Solas, Maite; Mateos, L; et al.
Revista: HIPPOCAMPUS
ISSN 1050-9631  Vol. 21  Nº 9  2011  págs. 999-1009
Autores: Aisa, Bárbara; Gil, Francisco Javier; Solas, Maite; et al.
Revista: JOURNAL OF ALZHEIMERS DISEASE
ISSN 1387-2877  Vol. 20   Nº 2  2010  págs. 659 - 668
Autores: Gil, Francisco Javier; Aisa, Bárbara; et al.
Revista: JOURNAL OF ALZHEIMERS DISEASE
ISSN 1387-2877  Vol. 22  Nº 3  2010  págs. 829 - 838
The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-ß levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.
Autores: Gil, Francisco Javier; Solas, Maite; et al.
Revista: Journal of Alzheimer s Disease
ISSN 1387-2877  Vol. 22  Nº 2  2010  págs. 405 - 413
Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-ß 1-42 (Aß1-42) levels and cognitive score. Furthermore, total-tau/(Aß1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aß1-42 ratio for early AD diagnosis in women.
Autores: Solas, Maite; Aisa, Bárbara; Mugueta, Carmen; et al.
Revista: NEUROPSYCHOPHARMACOLOGY
ISSN 0893-133X  Vol. 35  Nº 8  2010  págs. 1664 - 1673
There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease. Glucocorticoid secretion associated with early life stress may contribute to the variability of the aging process and to the development of neuro- and psychopathologies. Maternal separation (MS), a model of early life stress in which rats experience 3 h of daily separation from the dam during the first 3 weeks of life, was used to study the interactions between stress and aging. Young (3 months) MS rats showed an altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, depressive-like behavior in the Porsolt swimming test and cognitive impairments in the Morris water maze and new object recognition test that persisted in aged (18 months) rats. Levels of insulin receptor, phosphorylated insulin receptor and markers of downstream signaling pathways (pAkt, pGSK3 beta, pTau, and pERK1 levels) were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker ARC in MS aged rats compared with single MS or aged rats. It is interesting to note that there was a significant increase in the C99 : C83 ratio, A beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that in aged rats subjected to early life stress, there was an increase in the amyloidogenic processing of amyloid precursor protein (APP). These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of Alzheimer disease (AD). The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD.
Autores: Marcos, Beatriz; Cabero, M.; Solas, Maite; et al.
Revista: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
ISSN 1461-1457  Vol. 13  Nº 6  2010  págs. 775 - 784
A growing body of evidence supports the use of serotonin 5-HT6 receptor antagonists as a promising mechanism for treating cognitive dysfunction. We evaluated 5-HT6 receptor expression and associated biochemical mechanisms in the hippocampus of rats that had been trained in the Morris water maze (MWM), a spatial learning task. Training in the MWM induces a down-regulation of 5-HT6 receptor protein and mRNA receptor expression. The learning procedure or the administration of the selective 5-HT6 receptor antagonist SB-271046 induced an increase in pCREB1 levels while CREB2 levels were significantly reduced. However, although SB-271046 was able to improve retention in the MWM, no further changes in pCREB1 or CREB2 levels were found to be associated with the presence of the 5-HT6 receptor antagonist during the learning procedure. The MWM procedure significantly increased pERK1/2 levels and interestingly, further increases were seen when treating with SB-271046 during the MWM. These results suggest that, in the hippocampus, biochemical pathways associated with pERK1/2 expression, and not with the CREB family of transcription factors, seem to be related to the cognitive-enhancing properties of 5-HT6 receptor antagonists.
Autores: Solas, Maite; Bengoetxea, Xabier; Ferrero, H.; et al.
Libro:  Spatial, long-and short-term memory: functions, differences and effects of injury
2015  págs. 1 - 30
Memory is one of the earliest cognitive functions to show decline during aging and some neurodegenerative diseases and this decline has a social and economic impact on individuals, families, the health care system, and society as a whole. Therefore, scientists have been experimenting to find methods to prevent the memory loss associated with neurodegeneration. The main strategy involved in these experiments is the use of animal models to assess hippocampal-based spatial memory. This kind of memory encodes, stores, recognizes and recalls spatial information about the environment and the agent¿s orientation within it and it is essential for independence, safety and a good quality of life. In order to understand the pathophysiology of brain aging and to gain insight into the potential mechanisms underlying spatial memory dysfunctions many rodent behavioral tasks have been specifically designed, including Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze or T-maze. Among them, the most widely employed spatial working memory test is MWM. Theoretically, preclinical rodent cognitive testing would assess identical cognitive domains to those examined through neuropsychological testing in human. However, researchers need to be aware of the advantages as well as of the potential weaknesses of the available behavioral models in terms of their ability to model cognitive changes observed in human.
Autores: Puerta, Elena; Tordera, R.M.; Ramírez, M.J.; et al.
Libro:  Cognitive dysfunctions: biological basis, management of symptoms and long-term neurological implications
2014  págs. 63 - 86
Autores: Solas, Maite; Ramírez, M.J.;
Libro:  Gamma-aminobutyric acid (GABA): Biosynthesis, medicinal uses and health effects
2014  págs. 133 - 158
Autores: Solas, Maite; Ramírez, M.J.;
Libro:  Metabolic Syndrome and Neurological Disorders
2013  págs. 115 - 135

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