Publications (4)16.59 Total impact
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Article: Nrf2 participates in depressive disorders through an anti-inflammatory mechanism.
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ABSTRACT: A causative relationship between inflammation and depression is gradually gaining consistency. Because Nrf2 participates in inflammation, we hypothesized that Nrf2 could play a role in depressive disorders. In this study, we have observed that Nrf2 deletion in mice results in: (i) a depressive-like behavior evaluated as an increase in the immobility time in the tail-suspension test and by a decrease in the grooming time in the splash test, (ii) reduced levels of dopamine and serotonin and increased levels of glutamate in the prefrontal cortex, (iii) altered levels of proteins associated to depression such as VEGF and synaptophysin and (iv) microgliosis. Furthermore, treatment of Nrf2 knockout mice with the anti-inflammatory drug rofecoxib reversed their depressive-like behavior, while induction of Nrf2 by sulforaphane, in an inflammatory model of depression elicited by LPS, afforded antidepressant-like effects. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel antidepressive drugs.Psychoneuroendocrinology 04/2013; · 5.81 Impact Factor -
Article: Neurotoxicity induced by okadaic acid in the human neuroblastoma SH-SY5Y line can be differentially prevented by α7 and β2* nicotinic stimulation.
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ABSTRACT: A good model of neuronal death that reproduces the characteristic tau (τ) hyperphosphorylation of Alzheimeŕs disease is the use of okadaic acid (OA). The aim of this study was to determine the contribution of α7 and β2* nicotinic acetylcholine receptor (nAChR) subtypes to neuroprotection against OA in the SH-SY5Y cell line by using the selective α7 and β2* nAChR agonists PNU 282987 and 5-Iodo-A85380, respectively. The results of this study show that both α7 and β2* nAChR can afford neuroprotection against OA-induced neurotoxicity. Protection mediated by α7 nAChRs was independent of Ca(2+) and involved the intracellular signaling pathway Janus Kinase-2/Phosphatidylinositol-3-kinase/Akt. When Ca(2+) entry was promoted through the α7 nAChR by using the α7-selective positive allosteric modulator PNU 120596, protection was lost. By contrast, protection mediated by β2* nAChRs was Ca(2+) dependent and implicated the signaling pathways PI3K/Akt and extracellular regulated kinase 1/2. Both α7 and β2* nAChR activation converged on downregulation of GSK-3β and reduction of τ phosphorylation in cells undergoing cell death induced by OA. Therefore, targeting nAChR could offer a strategy for reducing neurodegeneration secondary to hyperphosphorylation of protein τ.Toxicological Sciences 06/2011; 123(1):193-205. · 4.65 Impact Factor -
Article: N-acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease.
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ABSTRACT: We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aβ peptide.European journal of medicinal chemistry 03/2011; 46(6):2224-35. · 3.27 Impact Factor -
Article: Chondroitin sulfate reduces cell death of rat hippocampal slices subjected to oxygen and glucose deprivation by inhibiting p38, NFκB and iNOS.
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ABSTRACT: The glycosaminoglycan chondroitin sulfate (CS) is a major constituent of the extracellular matrix of the central nervous system where it can constitute part of the perineuronal nets. Constituents of the perineuronal nets are gaining interest because they have modulatory actions on their neighbouring neurons. In this study we have investigated if CS could afford protection in an acute in vitro ischemia/reoxygenation model by using isolated hippocampal slices subjected to 60min oxygen and glucose deprivation (OGD) followed by 120min reoxygenation (OGD/Reox). In this toxicity model, CS afforded protection of rat hippocampal slices measured as a reduction of lactate dehydrogenase (LDH) release; maximum protection (70% reduction of LDH) was obtained at the concentration of 3mM. To evaluate the intracellular signaling pathways implicated in the protective effect of CS, we first analysed the participation of the mitogen-activated protein kinases (MAPKs) p38 and ERK1/2 by western blot. OGD/Reox induced the phosphorylation of p38 and dephosphorylation of ERK1/2; however, CS only inhibited p38 but had no effect on ERK1/2. Furthermore, OGD/Reox-induced translocation of p65 to the nucleus was prevented in CS treated hippocampal slices. Finally, CS inhibited iNOS induction caused by OGD/Reox and thereby nitric oxide (NO) production measured as a reduction in DAF-2 DA fluorescence. In conclusion, the protective effect of CS in hippocampal slices subjected to OGD/Reox can be related to a modulatory action of the local immune response by a mechanism that implies inhibition of p38, NFκB, iNOS and the production of NO.Neurochemistry International 02/2011; 58(6):676-83. · 2.86 Impact Factor
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2011
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Universidad Autónoma de Madrid
- Facultad de Medicina
Madrid, Madrid, Spain
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