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Posada Ayala, María

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María

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Posada Ayala

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Ciencias Experimentales

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Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease.
(Journal of Neuroinflammation, 2021) Ruiz Pérez, Gonzalo; Ruiz de Martín Esteban, Samuel; Marqués, Sharai; Aparicio, Noelia; Grande Rodríguez, Mª Teresa; Benito Cuesta, Irene; Martínez Relimpio, Ana María; Arnanz, M. Andrea; Tolón, Rosa María; Posada Ayala, María; Cravatt, Benjamin F.; Esteban, José A.; Romero, Julián; Palenzuela Muñoz, Rocío
Background: The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods: In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results: We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and longterm potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion: In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease
Endocannabinoid system modulation in peripheral blood mononuclear cells from dimethyl fumarate-treated multiple sclerosis patients.
(2021) Sánchez Sanz, Alicia; Posada Ayala, María; Sabín Muñoz, Julia; García Hernández, Ruth; Rodríguez de la Fuente, Ofir; Romero, Julián; García Merino, Antonio; Sánchez López, Antonio J
Background: The endocannabinoid system (ECS) consists of lipid metabolites, their receptors and the enzymes implicated in their synthesis and degradation. The ECS exerts anti-inflammatory and neuroprotective properties and its modulation has the potential of being a therapeutic target in Multiple Sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS, which has immunomodulatory effects although its mechanism of action is not yet fully understood. Objectives: To test if DMF could modulate the ECS in Peripheral Blood Mononuclear Cells (PBMCs) from MS patients. Methods: PBMCs from 11 Healthy Donors (HC) and 20 MS patients (at baseline and after 1 year of DMF treatment) were obtained by Ficoll density gradient centrifugation. Patients were clinically followed for 2 years; disease activity was assessed annually. The levels of the endocannabinoids 2-Arachidonoylglycerol (2-AG), Anandamide (AEA), Oleoylethanolamine (OEA) and Palmitoylethanolamine (PEA) were determined by Liquid chromatography–mass spectrometry (LC-MS), and normalized to the total amount of protein. Results: The median values (in pmol/g protein) of 2-AG and AEA were both similar between HC (361.42 for 2-AG; 63.62 for AEA) and patients at baseline (269.26 for 2-AG; 58.70 for AEA). After 1 year of treatment, no differences were found compared to baseline. However, there was a trend (p=0.07) towards an increase of 2-AG in patients that did not reach NEDA 3 on follow-up at 2 years. OEA and PEA levels were both lower at baseline (61.83 for OEA, p=0.01; 541.0 for PEA, p=0.001) compared to HC (190.35 for OEA; 1140.51 for PEA). After 1 year, PEA levels were unchanged (449.50, p=0.68), but OEA (115.39, p=0.04) increased to levels similar to those of HC. Conclusions: Our results confirm the dysregulation of the ECS in MS. Furthermore, they shed light on a new mechanism of action of DMF in MS, as it can modulate the ECS through OEA
The High Content of Quercetin and Catechin in Airen Grape Juice Supports Its Application in Functional Food Production.
(Foods, 2021) García Martínez, Daniel; Arroyo-Hernández, María; Posada Ayala, María; Santos Tejedor, Cruz
Ensuring healthy lives and well-being constitutes one of the Sustainable Development Goals of the UN 2030 agenda. Consequently, research into how natural products may promote health is essential for the new generation of nutraceuticals and functional foods that are in high demand today. Grape juice is a natural foodstuff composed of water, sugars, minerals, vitamins and a wide array of polyphenols. Polyphenols are bioactive compounds of great interest due to their antioxidant properties and benefits to health, supporting antimicrobial, anti-aging, and anticarcinogenic activity. The majority of grape juice produced in the world is used for the production of wine, although a small part is used in the food industry, mainly in baby food and sports drinks. The aim of this work is to determine the polyphenol content in the natural and concentrated juice of Airen grapes, the main white grape variety produced in Spain. For this, fresh juices from five grape varietals (Airen, Sauvignon Blanc, Gewürztraminer, Verdejo and Tempranillo) and concentrated Airen juice were analyzed and compared. Results showed similar contents of phenolic acids and stilbenes in all grape varietals studied, although the Airen variety demonstrated a higher concentration of two flavonoids: quercetin and catechin. It can be concluded that the grape juice concentration process negatively affects the stability of these compounds, causing a reduction in the polyphenol content that ranges between 54–71%, with the exception of quercetin and catechin.
Effect of p-Synephrine on Fat Oxidation Rate during Exercise of Increasing Intensity in Healthy Active Women.
(Nutrients, 2022) Gutiérrez Hellín, Jorge; Aguilar Navarro, Millán; Ruiz Moreno, Carlos; Muñoz Moreno, Alejandro; Amaro-Gahete, Francisco J.; López Samanés, Álvaro; Posada Ayala, María; Del Coso, Juan; Varillas Delgado, David
p-Synephrine is the principal alkaloid of bitter orange (Citrus aurantium). Several recent investigations have found that the intake of 2–3 mg/kg of p-synephrine raises fat oxidation rate during exercise of low-to-moderate intensity. However, these investigations have been carried out only with samples of male participants or mixed men/women samples. Therefore, the aim of this investigation was to study the effect of p-synephrine intake on fat oxidation during exercise of increasing intensity in healthy women. Using a double-blind, randomized experiment, 18 healthy recreationally active women performed two identical exercise trials after the ingestion of (a) 3 mg/kg of psynephrine and (b) 3 mg/kg of a placebo (cellulose). The exercise trials consisted of a ramp test (from 30 to 80% of maximal oxygen uptake; VO2max) on a cycle ergometer while substrate oxidation rates were measured at each workload by indirect calorimetry. In comparison to the placebo, the intake of p-synephrine increased resting tympanic temperature (36.1 ± 0.5 vs. 36.4 ± 0.4 °C p = 0.033, d = 0.87) with no effect on resting heart rate (p = 0.111) and systolic (p = 0.994) and diastolic blood pressure (p = 0.751). During exercise, there was no significant effect of p-synephrine on fat oxidation rate (F = 0.517; p = 0.484), carbohydrate oxidation rate (F = 0.730; p = 0.795), energy expenditure rate (F = 0.480; p = 0.833), heart rate (F = 4.269; p = 0.068) and participant’s perceived exertion (F = 0.337; p = 0.580). The maximal rate of fat oxidation with placebo was 0.26 ± 0.10 g/min and it was similar with p-synephrine (0.28 ± 0.08 g/min, p = 0.449, d = 0.21). An acute intake of 3 mg/kg of p-synephrine before exercise did not modify energy expenditure and substrate oxidation during submaximal aerobic exercise in healthy active women. It is likely that the increase in resting tympanic temperature induced by p-synephrine hindered the effect of this substance on fat utilization during exercise in healthy active women.
Effect of 3 and 6 mg/kg of caffeine on fat oxidation during exercise in healthy active females.
(Biology of Sport, 2023) Varillas Delgado, David; Aguilar Navarro, Millán; Muñoz Moreno, Alejandro; López Samanés, Álvaro; Ruiz-Moreno, Carlos; Posada Ayala, María; Amaro-Gahete, Francisco J.; Del Coso, Juan; Gutiérrez Hellín, Jorge
The aim of this study was to investigate the effect of 3 and 6 mg of caffeine per kg of body mass (mg/kg) on whole-body substrate oxidation during an incremental cycling exercise test in healthy active women. Using a double-blind placebo-controlled counterbalanced experimental design, 14 subjects performed three identical exercise trials after the ingestion of 3 or 6 mg/kg of caffeine or placebo. The exercise trials consisted of an incremental test on a cycle ergometer with 3-min stages at workloads from 30 to 70% of maximal oxygen uptake (VO2max). Substrate oxidation rates were measured by indirect calorimetry. During exercise, there was a significant effect of substance (F = 5.221; p = 0.016) on fat oxidation rate. In comparison to the placebo, 3 mg/kg of caffeine increased fat oxidation rates at 30 to 60% of VO2max (all p < 0.050) and 6 mg/kg at 30 to 50% of VO2max (all p < 0.050). There was also a significant effect of substance (F = 5.221; p = 0.016) on carbohydrate oxidation rate (F = 9.632; p < 0.001). In comparison to placebo, both caffeine doses decreased carbohydrate oxidation rates at 40 to 60% VO2max (all p < 0.050). The maximal rate of fat oxidation with placebo was 0.24 ± 0.03 g/min, which increased with 3 mg/kg to 0.29 ± 0.04 g/min (p = 0.032) and to 0.29 ± 0.03 with 6 mg/kg of caffeine (p = 0.042). Acute intake of caffeine improves the utilization of fat as a fuel during submaximal aerobic exercise in healthy active women with an effect of similar magnitude after the intake of 3 and 6 mg of caffeine per kg of body mass. Thus, the use of 3 mg/kg of caffeine would be more recommended than 6 mg/kg for women seeking increased fat utilization during submaximal exercise.
Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate.
(Scientific Reports, 2022) Sánchez‑Sanz, Alicia; Posada Ayala, María; Sabín‑Muñoz, Julia; Fernández‑Miranda, Ismael; ; Álvarez‑Lafuente, Roberto; Royuela, Ana; García‑Hernández, Ruth; Rodríguez‑De la Fuente, Ofir; Romero, Julián; García Merino, Antonio; Sánchez‑López, Antonio José; Aladro Benito, Yolanda
The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.
Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration.
(Acta Neuropathological Communications, 2021) Galán Ganga, M.; Rodríguez Cueto, C.; Merchán Rubira, J.; Hernández, F.; Ávila, J.; Posada Ayala, María; Lanciego, J.L.; Luengo, E.; López, M. G.; Rábano, A.; Fernández Ruiz, J.; Lastres Becker, I.
Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein, for which there is still no effective treatment. Therefore, new pharmacological targets are being sought, such as elements of the endocannabinoid system (ECS). We analysed the occurrence of changes in the ECS in tauopathies and their implication in the pathogenesis. By integrating gene expression analysis, immunofluorescence, genetic and adeno-associated virus expressing TAU mouse models, we found a TAU-dependent increase in CB2 receptor expression in hippocampal neurons, that occurs as an early event in the pathology and was maintained until late stages. These changes were accompanied by alterations in the endocannabinoid metabolism. Remarkably, CB2 ablation in mice protects from neurodegeneration induced by hTAU P301L overexpression, corroborated at the level of cognitive behaviour, synaptic plasticity, and aggregates of insoluble TAU. At the level of neuroinflammation, the absence of CB2 did not produce significant changes in concordance with a possible neuronal location rather than its classic glial expression in these models. These findings were corroborated in post-mortem samples of patients with Alzheimer’s disease, the most common tauopathy. Our results show that neurons with accumulated TAU induce the expression of the CB2 receptor, which enhances neurodegeneration. These results are important for our understanding of disease mechanisms, providing a novel therapeutic strategy to be investigated in tauopathies