Person: Navarro González De Mesa, Elisa
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First Name
Elisa
Last Name
Navarro González De Mesa
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
5 results
Search Results
Now showing 1 - 5 of 5
Item Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD-Hallmarks in Hippocampal Organotypic Cultures(Molecular Neurobiology, 2015) Buendía, I.; Parada, E.; Navarro González De Mesa, Elisa; León Martínez, Rafael; Negredo Madrigal, Pilar; Egea Máiquez, Francisco Javier; García López, ManuelaMelatonin is a neurohormone whose levels are significantly reduced or absent in Alzheimer's disease (AD) patients. In these patients, acetylcholinesterase inhibitors (AChEI) are the major drug class used for their treatment; however, they present unwanted cholinergic side effects and have provided limited efficacy in clinic. Because combination therapy is being extensively used to treat different pathological diseases such as cancer or acquired immune deficiency syndrome, we posed this study to evaluate if melatonin in combination with an AChEI, galantamine, could provide beneficial properties in a novel in vitro model of AD. Thus, we subjected organotypic hippocampal cultures (OHCs) to subtoxic concentrations of β-amyloid (0.5 μM βA) plus okadaic acid (1 nM OA), for 4 days. This treatment increased by 95 % cell death, which was mainly apoptotic as shown by positive TUNEL staining. In addition, the combination of βA/OA increased Thioflavin S aggregates, hyperphosphorylation of Tau, oxidative stress (increased DCFDA fluorescence), and neuroinflammation (increased IL-1β and TNFα). Under these experimental conditions, melatonin (1-1000 nM) and galantamine (10-1000 nM), co-incubated with the toxic stimuli, caused a concentration-dependent neuroprotection; maximal neuroprotective effect was achieved at 1 μM of melatonin and galantamine. Most effective was the finding that combination of sub-effective concentrations of melatonin (1 nM) and galantamine (10 nM) provided a synergic anti-apoptotic effect and reduction of most of the AD-related pathological hallmarks observed in the βA/OA model. Therefore, we suggest that supplementation of melatonin in combination with lower doses of AChEIs could be an interesting strategy for AD patients.Item Compounds derived from 3-Alkylamino-1H-indole acrylate, and the use thereof in the treatment of neurodegenerative diseases.(2015) León Martínez, Rafael; Buendia Abaitua, Izaskun; Navarro González De Mesa, Elisa; Michalska Dziama, Patrycja; Gameiro Ros, Isabel Marina; López Vivo, Alicia; Egea Máiquez, Francisco Javier; García López, Manuela; García García, Juan Antonio; Fundación para la investigación biomédica del Hospital Universitario de La PrincesaThe inventions relates to the methods for producing derivatives of 3-alkylamino-1-H indole acrylate (I) with transcription factor Nrf2-inducing activity, free radical scavenging activity and neuroprotective ability. The invention also relates to the use of derivatives according to the invention for the treatment of diseases, the pathogenesis of which involves oxidative stress, or diseases involving the deregulation of the activity of phase II genes activated by the factor Nrf2 such as Alzheimer´s disease, Parkinson´s disease, Huntington´s disease, multiple sclerosis, ictus or amyotrophic lateral sclerosis.Item Heme-Oxygenase I and PCG-1α Regulate Mitochondrial Biogenesis via Microglial Activation of Alpha7 Nicotinic Acetylcholine Receptors Using PNU282987(Antioxidants and Redox Signaling, 2017) Navarro González De Mesa, Elisa; García López, ManuelaAims: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through α7 nAChR. Results: Primary glial cultures treated with the α7 nicotinic agonist PNU282987 increased their mitochondrial mass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) was silenced. More specifically, microglia of animals treated intraperitoneally with the α7 nAChR agonist PNU282987 (10 mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysMcre-Hmox1Δ/Δ and PGC-1α-/- animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels. Innovation: Increases in microglial mitochondrial mass and metabolism can be achieved via α7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1α. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers. Conclusion: α7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1α. These effects could be of potential benefit in the context of NDDs. Antioxid. Redox Signal. 27, 93-105.Item Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction(Biochemical Pharmacology, 2015) Navarro González De Mesa, Elisa; Buendía, Izaskun; Parada, Esther; León Martínez, Rafael; Jansen-Duerr, Pidder; Pircher, Haymo; Egea, Javier; García López, ManuelaSubchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimer's or Parkinson's disease. This study was designed to evaluate the potential protective role of α7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1μM) and lipopolysaccharide (1ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The α7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by α-bungarotoxin and tin protoporphyrin, indicating the participation of α7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. α7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction.Item Microglial HO‐1 induction by curcumin provides antioxidant, antineuroinflammatory, and glioprotective effects(Molecular Nutrition & Food Research, 2015) Parada, Esther; Buendia, Izaskun; Navarro González De Mesa, Elisa; Avendaño, Carlos; Egea, Javier; García López, ManuelaScope: We have studied if curcumin can protect glial cells under an oxidative stress and inflammatory environment, which is known to be deleterious in neurodegeneration. Methods and results: Primary rat glial cultures exposed to the combination of an oxidative (rotenone/oligomycin A) and a proinflammatory LPS stimuli reduced by 50% glial viability. Under these experimental conditions, curcumin afforded significant glial protection and reduction of reactive oxygen species; these effects were blocked by the HO-1 inhibitor tin protoporphyrin-IX (SnPP). These findings correlate with the observation that curcumin induced the antioxidative protein HO-1. Most interesting was the observation that the glial protective effects related to HO-1 induction were microglial specific as shown in glial cultures from LysM(Cre) Hmox(∆/∆) mice where curcumin lost its protective effect. Under LPS conditions, curcumin reduced the microglial proinflammatory markers iNOS and tumor necrosis factor, but increased the anti-inflammatory cytokine IL4. Analysis of the microglial phenotype showed that curcumin favored a ramified morphology toward a microglial alternative activated state against LPS insult also by a HO-1-dependent mechanism. Conclusion: The curry constituent curcumin protects glial cells and promotes a microglial anti-inflammatory phenotype by a mechanism that implicates HO-1 induction; these effects may have impact on brain protection under oxidative and inflammatory conditions.