Reduction in Hippocampal Amyloid-ß Peptide (Aß) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.

Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-ß peptides (Aßs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aß levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aß25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aß-degrading enzymes associated with these GPE-related effects. GPE prevented the Aß-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aß insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aß levels through modulation of levels and/or activity of Aß proteases.

Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease.

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood-brain barrier to reach the target areas in the brain or to regulate the function of the blood-brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood-brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

The combined effect of front-of-package labels and influencer recommendations on food choice decisions.

Many governments have adopted front-of-pack nutrition labels (FOP labels) that give advice about how healthy a product is. An increasing number of digital food influencers are also informing consumers about the nutritional quality of products and promoting healthy consumption. In this context, the current study analyzes how both sources of information come together to affect purchase intention. Drawing on congruence theory, we propose that the influencer's recommendation reinforces the effect of the FOP label when there is congruence between the two; however, consumers clearly prefer to follow the recommendation of the influencer over the FOP label when the information sources are non-congruent. We develop a between-subjects experimental design in which the level of congruence between the two information sources is manipulated. The effect of the influencer on purchase intention is mediated by the credibility of the FOP label. A second study confirms the superiority of the influencer effect observed in the first study.

Cambios en la alimentación causados por la parosmia secundaria a COVID-19 en la población adulta residente en Chile durante el año 2021

Introducción: existe escasa evidencia de la prevalencia de disfunciones olfatorias, como la parosmia post infección de COVID-19, en población chilena y a la vez como esta afecta la alimentación y nutrición de los sujetos que la padecen. Objetivo: describir los cambios en la alimentación causados por la parosmia secundaria a COVID-19 según las características sociodemográficas en población adulta residente en Chile durante el año 2021. Métodos: estudio cuantitativo transversal descriptivo con una muestra de 542 participantes, se aplicó un cuestionario de autoría propia, en el que se consideran datos sociodemográficos, factores condicionantes en la alimentación, cambios en la alimentación y técnicas culinarias. Resultados: se reportó una prevalencia de parosmia del 65%, afectando principalmente a las mujeres con un 85,8%, con un promedio de edad de 32 ± 9 años y 33 ± 9 años para mujeres y hombres respectivamente. Los principales cambios alimentarios fueron una disminución de la ingesta de carnes, huevos y comida rápida y un aumento del consumo de verduras, además se observó una menor diversificación en las técnicas culinarias utilizadas para la cocción de los alimentos. Conclusión: se reportaron cambios importantes en la alimentación de los sujetos con parosmia, lo que pone en evidencia la necesidad de investigar como esto afecta el estado nutricional y calidad de vida de los sujetos que la padecen.

Introduction: there is little evidence of the prevalence of olfactory dysfunctions, such as post-COVID-19 infection parosmia, in the Chilean population and at the same time how it affects the food and nutrition of the subjects who suffer from it. Objective: to describe the changes in the diet caused by parosmia secondary to COVID-19 according to sociodemographic characteristics in the adult population residing in Chile during the year 2021. Methods: descriptive cross-sectional quantitative study with a sample of 542 participants, a questionnaire of own authorship, in which sociodemographic data, conditioning factors in food, changes in food, and culinary techniques are considered. Results: a prevalence of parosmia of 65% was reported, mainly affecting women at 85.8%, with an average age of 32 and 33 years for women and men, respectively. The main dietary changes were a decrease in the intake of meat, eggs, and fast food and an increase in the consumption of vegetables, in addition, less diversification was observed in the culinary techniques used for cooking food. Conclusion: important changes were reported in the diet of subjects with parosmia, which highlights the need to investigate how this affects the nutritional status and quality of life of subjects who suffer from it.

Small Synthetic Hyaluronan Disaccharide BIS014 Mitigates Neuropathic Pain in Mice.

Neuropathic pain (NP) is a challenging condition to treat, as the need for new drugs to treat NP is an unmet goal. We investigated the analgesic potential of a new sulfated disaccharide compound, named BIS014. Oral administration (p.o.) of this compound induced ameliorative effects in formalin-induced nociception and capsaicin-induced secondary mechanical hypersensitivity in mice, but also after partial sciatic nerve transection (spared nerve injury), chemotherapy (paclitaxel)-induced NP, and diabetic neuropathy induced by streptozotocin. Importantly, BIS014, at doses active on neuropathic hypersensitivity (60 mg/kg/p.o.), did not alter exploratory activity or motor coordination (in the rotarod test), unlike a standard dose of gabapentin (40 mg/kg/p.o.) which although inducing antiallodynic effects on the NP models, it also markedly decreased exploration and motor coordination. In docking and molecular dynamic simulation studies, BIS014 interacted with TRPV1, a receptor involved in pain transmission where it behaved as a partial agonist. Additionally, similar to capsaicin, BIS014 increased cytosolic Ca2+ concentration ([Ca2+]c) in neuroblastoma cells expressing TRPV1 receptors; these elevations were blocked by ruthenium red. BIS014 did not block capsaicin-elicited [Ca2+]c transients, but inhibited the increase in the firing rate of action potentials in bradykinin-sensitized dorsal root ganglion neurons stimulated with capsaicin. Perspective: We report that the oral administration of a new sulfated disaccharide compound, named BIS014, decreases neuropathic pain from diverse etiology in mice. Unlike the comparator gabapentin, BIS014 does not induce sedation. Thus, BIS014 has the potential to become a new efficacious non-sedative oral medication for the treatment of neuropathic pain.

KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

Cytotoxicity Models in Chromaffin Cells to Evaluate Neuroprotective Compounds.

Primary cultures of bovine chromaffin cells are considered a good model to evaluate potential neuroprotective compounds for two major reasons: (i) they share many common features to neurons as they synthesize, store, and release neurotransmitters; they are excitable cells that express voltage-dependent calcium, potassium, and sodium channels; they express different neuronal receptor subtypes; and (ii) they can be easily cultured in high quantities from adult animals; as adult para-neurons, they can be used to reproduce different neurodegenerative-like cytotoxicity models. In this chapter, we describe protocols to mimic calcium overload (veratridine and thapsigargin) and oxidative stress (rotenone plus oligomycin-A and 6-hydroxydopamine) to evaluate potential neuroprotective compounds.

[Maxillary sinus lesions and their association with apical lesions observed by cone beam computed tomography. A retrospective cross-sectional study]. / Lesiones del seno maxilar y su asociación con lesiones apicales observadas por tomografía computarizada de haz cónico. Un estudio transversal retrospectivo.

Introduction: Through cone beam computed tomography, alterations in the maxillary sinuses, such as opacities, space occupation and thickening of the mucosa, can be observed. Some factors contribute to this thickening, standing out among dental factors, periodontitis, apical pathology and endodontic treatments. Objective: To evaluate the association between changes observed in the maxillary sinuses and apical lesions using cone beam computed tomography. Materials and methods: It was a descriptive study with a retrospective and cross-sectional, correlational, field, non-experimental design. The sample consisted of 115 tomographic volumes obtained using Planmeca ProMax 3D Classic equipment (Planmeca, Helsinki, Finland). The presence/absence of endodontic treatment in the present posterior teeth, presence/absence of periapical lesion associated with these teeth, the size of the periapical lesion, presence/absence of alteration in the maxillary sinus and its thickness were evaluated. Results: Apical lesions were observed that averaged a size of 3.32 ± 1.82 mm, and almost half (44.35%) presented between 2 and 4 mm in size. The main alteration of the maxillary sinus that was observed was the thickening of the mucosa (58.26%). The average thickness of the thickening of the sinus mucosa was 3.51 ± 1.78 mm, with 72.17% of the cases with thickening greater than 2 mm. Conclusion: There was an association between the changes observed in the maxillary sinuses and apical lesions. The larger and closer the lesion was to the sinus, the greater the thickening of the sinus mucosa.

Sustainability and Gender Perspective in Food Innovation: Foods and Food Processing Coproducts as Source of Macro- and Micro-Nutrients for Woman-Fortified Foods.

Micro- and macro-nutrient deficiencies among women are considered a global issue that the food industry has not adequately considered until recently. The industry must provide and guarantee a diversity of food products worldwide that allow women to get a correct and balanced diet according their life stage. The food industry must focus on this challenge within a framework of sustainable production, minimizing the use of natural resources and avoiding the emission of waste and pollutants throughout the life cycle of food. Food coproducts are presented as potential bioactive functional compounds which can be useful for technological purposes, due to the fact that they can serve as non-chemical, natural and health-improving food ingredients. In this review, we focus on the potential use of food processing coproducts which must be part of a strategy to promote and improve women's health and well-being. This knowledge will make it possible to select potential ingredients from coproducts to be used in the fortification of foods intended for consumption by females and to introduce sustainability and gender perspectives into food innovation. The attainment of fortifications for foods for women has to be linked to the use of sustainable sources from food coproducts in order to be economically viable and competitive.

Microglial Hemoxygenase-1 Deletion Reduces Inflammation in the Retina of Old Mice with Tauopathy.

Tauopathies such as Alzheimer's disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer's patients, the inducible enzyme heme oxygenase 1 (HO-1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain. In this context, we evaluated how the lack of microglial HO-1, using mice that do not express HO-1 in microglia (HMO-KO), impacts retinal macro and microgliosis of aged subjects (18 months old mice) subjected to tauopathy by intrahippocampal delivery of AAV-hTauP301L (TAU). Our results show that although tauopathy, measured as anti-TAUY9 and anti-AT8 positive immunostaining, was not observed in the retina of WT-TAU or HMO-KO+TAU mice, a morphometric study of retinal microglia and macroglia showed significant retinal changes in the TAU group compared to the WT group, such as: (i) increased number of activated microglia, (ii) retraction of microglial processes, (iii) increased number of CD68+ microglia, and (iv) increased retinal area occupied by GFAP (AROA) and C3 (AROC3). This retinal inflammatory profile was reduced in HMO-KO+TAU mice. Conclusion: Reduction of microglial HO-1 could be beneficial to prevent tauopathy-induced neuroinflammation.

Un-biased housekeeping gene panel selection for high-validity gene expression analysis.

Differential gene expression normalised to a single housekeeping (HK) is used to identify disease mechanisms and therapeutic targets. HK gene selection is often arbitrary, potentially introducing systematic error and discordant results. Here we examine these risks in a disease model of brain hypoxia. We first identified the eight most frequently used HK genes through a systematic review. However, we observe that in both ex-vivo and in vivo, their expression levels varied considerably between conditions. When applying these genes to normalise expression levels of the validated stroke target gene, inducible Nox4, we obtained opposing results. As an alternative tool for unbiased HK gene selection, software tools exist but are limited to individual datasets lacking genome-wide search capability and user-friendly interfaces. We, therefore, developed the HouseKeepR algorithm to rapidly analyse multiple gene expression datasets in a disease-specific manner and rank HK gene candidates according to stability in an unbiased manner. Using a panel of de novo top-ranked HK genes for brain hypoxia, but not single genes, Nox4 induction was consistently reproduced. Thus, differential gene expression analysis is best normalised against a HK gene panel selected in an unbiased manner. HouseKeepR is the first user-friendly, bias-free, and broadly applicable tool to automatically propose suitable HK genes in a tissue- and disease-dependent manner.

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 µM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 µM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.

Echocardiographic 60-day mortality markers in patients hospitalized in intensive care for COVID-19.

BACKGROUND: Coronavirus disease COVID-19 produces a predominantly pulmonary affection, being cardiac involvement an important component of the multiorganic dysfunction. At the moment there are few reports about the behavior of echocardiographic images in the patients who have the severe forms of the disease. OBJECTIVE: Identify the echocardiographic prognostic markers for death within 60 days in patients hospitalized in intensive care. METHODS: A single-center prospective cohort was made with patients hospitalized in intensive care for COVID-19 confirmed via polymerase chain reaction who got an echocardiogram between May and October 2020. A Cox multivariate model was plotted reporting the HR and confidence intervals with their respective p values for clinical and echocardiographic variables. RESULTS: Out of the 326 patients included, 153 patients got an echocardiogram performed on average 6.8 days after admission. The average age was 60.7, 47 patients (30.7%) were females and 67 (44.7%) registered positive troponin. 91 patients (59.5%) died. The univariate analysis identified TAPSE, LVEF, pulmonary artery systolic pressure, acute cor pulmonale, right ventricle diastolic dysfunction, and right ventricular dilatation as variables associated with mortality. The multivariate model identified that the acute cor pulmonale with HR= 4.05 (CI 95% 1.09 - 15.02, p 0.037), the right ventricular dilatation with HR= 3.33 (CI 95% 1.29 - 8.61, p 0.013), and LVEF with HR= 0.94 (CI 95% 0.89 - 0.99, p 0.020) were associated with mortality within 60 days. CONCLUSIONS: In patients hospitalized in the intensive care unit for COVID-19, the LVEF, acute cor pulmonale and right ventricular dilatation are prognostic echocardiographic markers associated with death within 60 days.

Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.

Flexible treatment of gestational diabetes mellitus adjusted according to intrauterine fetal growth versus treatment according to strict maternal glycemic parameters: a randomized clinical trial.

INTRODUCTION: To compare the conventional treatment of gestational diabetes mellitus (GDM) with flexible treatment according to the measurement of fetal abdominal circumference (AC) in daily clinical practice. RESEARCH DESIGN AND METHODS: Two hundred and sixty pregnant women diagnosed with GDM before week 34 were randomly placed in two groups: a control group, treated according to maternal capillary glycemia, and an experimental group, treated according to ultrasound parameters of fetal growth. The glycemic targets in the control group were blood glucose levels when fasting and 1 hour postprandial (<95/140 mg/dL). In the experimental group, glycemic targets depended on the percentile (p) of fetal AC: if AC p <75th, then blood glucose targets when fasting and at 1 hour postprandial were <120/180 mg/dL; and if AC p ≥75th, then the glycemic targets were <80/120 mg/dL. The follow-up of both groups was scheduled according to the GDM protocol of our diabetes and gestation unit. RESULTS: The study was completed by 246 pregnant women, 125 in the control group and 121 in the experimental group. In the experimental group, insulin treatment and neonatal hypoglycemia were significantly lower (p=0.018 and p 0.035, respectively). No differences were observed in large and small infants according to gestational age. However, macrosomic infants were less frequent in the experimental group, although this difference did not reach statistical significance. In terms of gestation complications, the type of delivery and its complications and the rest of the neonatal complications analyzed, no significant differences were observed. CONCLUSIONS: The treatment of flexible GDM according to the measurement of fetal AC is safe for the mother and the fetus and almost halves the number of pregnant women who require insulin treatment, without increasing the number of ultrasound checks or medical visits.

Intracellular calcium and inflammatory markers, mediated by purinergic stimulation, are differentially regulated in monocytes of patients with major depressive disorder.

The P2X7 receptor (P2X7R) is a ligand-gated ion channel that is being recognized as a major player in neuropsychiatric disorders such as Major Depressive Disorder (MDD). P2X7R activation is triggered by high extracellular ATP concentrations, leading to channel opening and inducing an increase in cytosolic calcium concentration ([Ca2+]c), that activates the inflammatory pathway. Those receptors are expressed not only in CNS cells but also in peripheral blood cells, where they are activated in response to inflammatory molecules such as bacterial lipopolysaccharide (LPS). LPS induced-tissue damage promotes an elevation of extracellular ATP, triggering the NRLP3-inflammasome assembly and activation that, sequentially, induces caspase-1 cleavage and IL-1ß processing and secretion. In this context, we attempt to understand the role of P2X7R in [Ca2+]c homeostasis regulation, inflammasome expression and its pharmacological modulation in MDD. For this purpose, monocytes were isolated from peripheral blood of MDD patients and [Ca2+]c was monitored with the intracellular probe Fura-2. Our results point out to P2X7R as the responsible of the Ca2+ imbalance, as well as TNF-α-dependent activation of caspase-1 in MDD patients. In addition, P2X7R blockade with its specific antagonist, JNJ-47965567, reduces the Ca2+ entry upon Bz-ATP exposure. Altogether, our results point that MDD patients have both, Ca2+ homeostasis alteration and an inflammatory status, which promote an independent-inflammasome activation of caspase-1. Therefore, we propose the pharmacological modulation of P2X7R as a therapeutic approach against MDD symptoms.

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals.

We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the "Cholinergic anti-inflammatory pathway", we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1ß and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.