Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer's Disease Patients

Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer's disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD

Relevance of metalloproteinase-9 in depression: a study in transgenic animal models

Trabajo presentado en el 19th National Meeting of the Spanish Society of Neuroscience, celebrado en Lleida (España) del 03 al 05 de noviembre de 2021

Antidepressant-like effect of cannabidiol in an animal model induced by lipopolysaccharide administration

Trabajo presentado en la 20ª Reunión Anual de la Sociedad Española de Investigación sobre Cannabinoides, celebrado en Barcelona del 21 al 23 de noviembre de 2019

Implicación de la metaloproteinasa-9 en la depresión y en el efecto antidepresivo

Trabajo presentado en el 8ª Laboratorio de Ideas. Impacto de la pandemia COVID-19, celebrado en modalidad virtual del 25 al 27 de mayo de 2021

Resveratrol upregulates the expression of antioxidant genes inimmortalized AD lymphocytes

Trabajo presentado en el XI Simposi de Neurobiologia: Future technical advances, organizado por la Socitat Catalana de Biologia, en Barcelona, los días 12 y 13 de noviembre de 2018Alzheimer’s disease (AD) is the most common neurodegenerative disorder and first cause of dementia all over the world. It is characterized by a progressive neuronal loss. The main risk factor for developing AD is the age. Major pathological hallmarks include extracellular deposits of amyloid protein and intracellular deposits of neurofibrillary tau protein. AD brain also shows alterations developed in aged brain such as oxidative stress and inflammation. The study used immortalized lymphocytes from patients of sporadic AD and age-matched healthy controls (HC) with the following aims: First, analyze gene expression of oxidative stress and aging-related pathways in AD and HC lymphoblast cell lines. Next, investigate the potential role of resveratrol as antiaging and protective agent through the induction of further gene expression changes. Finally, establish the different sensitivity between the human immortalized lymphocyte cell lines and the human neuroblastoma cell line SH-SY5Y to the hormetic agent resveratrol and to oxidative stress inductors. Real-time PCR showed that oxidative stress and aging-related genes were differentially expressed in AD lymphoblasts compared to HC lymphoblasts with increases in CASP1, TXNIP, VPS13C, GPX1, PRDX5, SOD2, and decrease in CCS expression. Resveratrol incubated for 18h at concentration of 10, 20 or 50µM induced a general upregulation of antioxidant and detoxifying genes such as: CAT, NFE2L2, GSTZ1, and CCS, in both HC and AD lymphoblasts. Resveratrol also induced the expression of the anti-aging mitochondrial sirtuin SIRT3. At the concentrations tested, resveratrol was not cytotoxic to lymphoblast or SH-SY5Y neuroblastoma cultures, although the later were more sensitive to oxidative injuries. This study supports that immortalized lymphocytes is a suitable cell system to analyze molecular alterations of pathways common to non-neural and neural cells. Furthermore, resveratrol upregulation of antioxidant genes may contribute to improve physiological processes in aging and AD.Supprted by grants: SAF2016‐77703, MINECO and ERDF; 2017-SGR-106, AGAURPeer reviewe

Molecular signaling mechanisms for the antidepressant effects of NLX-101, a selective cortical 5-HT1A receptor biased agonist

Depression is the most prevalent of the mental illnesses and serotonin (5-hydroxytryptamine, 5-HT) is considered to be the major neurotransmitter involved in its etiology and treatment. In this context, 5-HT1A receptors have attracted interest as targets for therapeutic intervention. Notably the activation of presynaptic 5-HT1A autoreceptors delays antidepressant effects whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 (also known as F15599) is a selective biased agonist which exhibits preferred activation of cortical over brain stem 5-HT1A receptors. Here, we used behavioral, neurochemical and molecular methods to examine the antidepressant-like effects in rats of a single dose of NLX-101 (0.16 mg/kg, i.p.). NLX-101 reduced immobility in the forced swim test when measured 30 min but not 24 h after drug administration. NLX-101 increased extracellular concentrations of glutamate and dopamine in the medial prefrontal cortex, but no changes were detected in the efflux of noradrenaline or 5-HT. NLX-101 also produced an increase in the activation of pmTOR, pERK1/2 and pAkt, and the expression of PSD95 and GluA1, which may contribute to its rapid antidepressant action.This research was funded by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación, FIS grant number Pl19/00170 that was co-funded by the European Regional Development Fund (‘A way to build Europe’), the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00), and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (CIBERSAM CB/07/09/0029). E.F.-Z. was recipient of a predoctoral fellowship from the Universidad de Cantabria (Spain). J.S. has a predoctoral contract from the CIBERSAM, Spain. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI

Molecular and neurochemical aspects of the antidepressant effects of NLX-101, a selective cortical 5-HT1A receptor biased agonist

Trabajo presentado en Cell symposia: the biology of neuropsychiatric disorders, celebrada en Sitges (Barcelona) del 15 al 17 de mayo de 2022.Serotonin is considered to be the major neurotransmitter involved in depression and its treatment. Thus, 5-HT receptors have attracted interest as targets for therapeutic intervention. Notably, the activation of presynaptic 5-HT1A autoreceptors slows down the antidepressant effects of serotonin reuptake inhibitors whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 exhibits preferential activation of cortical and brain stem 5-HT1A receptors. Here we used behavioral, neurochemical and molecular methods to examine its antidepressant effects. NLX-101 (0.16 mg/kg) reduced immobility in the forced swim test when measured 30 min (albeit not 24 h and 7 days) after drug administration. NLX-101 increased the dialysate dopamine and glutamate in the medial prefrontal cortex, but no changes were observed in the prefrontal output of noradrenaline and serotonin. NLX-101 also produced a rapid increase in the synthesis of pmTOR, pERK1/2 and pGluA1, which may contribute to its rapid antidepressant action.Instituto de Salud Carlos III, FIS grant number Pl19/00170 that was co-funded by the European Regional Development Fund (‘A way to build Europe’), the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-BI00), and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (CIBERSAM CB/07/09/0029)

Molecular and neurochemical aspects of the antidepressant effects of NLX-101, a selective cortical 5-HT1A receptor biased agonist

Trabajo presentado en Cell symposia: the biology of neuropsychiatric disorders, celebrada en Sitges (Barcelona) del 15 al 17 de mayo de 2022.Serotonin is considered to be the major neurotransmitter involved in depression and its treatment. Thus, 5-HT receptors have attracted interest as targets for therapeutic intervention. Notably, the activation of presynaptic 5-HT1A autoreceptors slows down the antidepressant effects of serotonin reuptake inhibitors whereas the stimulation of postsynaptic 5-HT1A heteroreceptors is needed for an antidepressant action. NLX-101 exhibits preferential activation of cortical and brain stem 5-HT1A receptors. Here we used behavioral, neurochemical and molecular methods to examine its antidepressant effects. NLX-101 (0.16 mg/kg) reduced immobility in the forced swim test when measured 30 min (albeit not 24 h and 7 days) after drug administration. NLX-101 increased the dialysate dopamine and glutamate in the medial prefrontal cortex, but no changes were observed in the prefrontal output of noradrenaline and serotonin. NLX-101 also produced a rapid increase in the synthesis of pmTOR, pERK1/2 and pGluA1, which may contribute to its rapid antidepressant action.Instituto de Salud Carlos III, FIS grant number Pl19/00170 that was co-funded by the European Regional Development Fund (‘A way to build Europe’), the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-BI00), and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (CIBERSAM CB/07/09/0029)

Brain matrix metalloproteinase-9 activity is altered in the corticosterone mouse model of depression

Major depressive disorder is a highly prevalent psychiatric condition. Metalloproteinase 9 (MMP-9), a gelatinase involved in synaptic plasticity, learning and memory processes, is elevated in both chronic stress animal models and human peripheral blood samples of depressed patients. In this study we have evaluated the MMP-9 activity and protein expression in brain areas relevant to depression using the chronic corticosterone mouse model of depression. These mice show a depressive- and anxious-like behaviour. The MMP-9 activity and protein levels are significantly elevated in both the hippocampus and the cortex, and nectin-3 levels are lower in these brain areas in this model. In particular, these mice display an increased gelatinase activity in the CA1 and CA3 subfields of the hippocampus and in the internal layer of the prefrontal cortex. Moreover, the immobility time in the tail suspension test presents a positive correlation with the cortical MMP-9 activity, and a negative correlation with nectin-3 levels. In conclusion, the chronic corticosterone model of depression leads to an increase in the protein expression and activity of MMP-9 and a reduction of its substrate nectin-3 in relevant areas implicated in this disease. The MMP-9 activity correlates with behavioural despair in this model of depression. All these findings support the role of MMP-9 in the pathophysiology of depression, and as a putative target to develop novel antidepressant drugs.This research was supported by the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer’s Disease Patients

Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer’s disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD.This research was funded by Spanish MINECO and FEDER, grant number SAF2016-75508; Catalan Autonomous Government AGAUR, grant number 2017-SGR-106; and the CERCA Programme/Generalitat de Catalunya.Peer reviewe