Person:
Navarro González De Mesa, Elisa

First Name

Elisa

Last Name

Navarro González De Mesa

URI

https://hdl.handle.net/20.500.14352/79321

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Bioquímica y Biología Molecular

Area

Bioquímica y Biología Molecular

Identifiers

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Now showing 1 - 8 of 8

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; López Vivo, Alicia; Egea Máiquez, Francisco Javier; García López, Manuel; García García, Juan Antonio; Fundacioó para la investigación biomédica del Hospital Universitario de La Princesa
The 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.
Compuestos derivados de acrilato de 3-alquilamino-1H-indolilo y su uso en el tratamiento de las enfermeadades neurodegenerativas
(2016) León Martínez, Rafael; Buendia Abaitua, Izaskun; Navarro González De Mesa, Elisa; Michalska Dziama, Patrycja; Gameiro Ros, Isabel; Egea Máiquez, Franisco Javier; García Lopez, Manuela; García García, Juan Antonio; Fundacion para la investigacion biomedica del Hospital Universitario de La Princesa
The invent relates to the methods for producing derivates of 3-alkylamino-1H-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 of treatment of diseases, the pathogenesis of which involves oxidative stress, or diseases involving the deregulationof 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.
New melatonin–cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection
(Future Medicinal Chemistry, 2015) Buendia, Izaskun; Navarro González De Mesa, Elisa; Michalska Dziama, Patrycja; Gameiro, Isabel; Egea, Javier; Abril, Sheila; López, Alicia; González-Lafuente, Laura; G. López, Manuela; León Martínez, Rafael
Neurodegenerative diseases share many pathological pathways, such as abnormal protein aggregation, mitochondrial dysfunction, extensive oxidative stress and neuroinflammation. Cells have an intrinsic mechanism of protection, the Nrf2 transcriptional factor, known as the master regulator of redox homeostasis. Results: Based on the common features of these diseases we have designed a multi-target hybrid structure derived from melatonin and ethyl cinnamate. The obtained derivatives were Nrf2 inducers and potent-free radical scavengers. These new compounds showed a very interesting neuroprotective profile in several in vitro models of oxidative stress, Alzheimer's disease and brain ischemia. Conclusion: We have designed a new hybrid structure with complementary activities. We have identified compound 5h as an interesting Nrf2 inducer, very potent antioxidant and neuroprotectant.
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, Manuela
Melatonin 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.
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 Princesa
The 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.
Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases
(Pharmacology & Therapeutics, 2016) Buendia, Izaskun; Michalska Dziama, Patrycja; Navarro González De Mesa, Elisa; Gameiro, Isabel; Egea, Javier; León Martínez, Rafael
Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is increasing, the prevalence of these diseases is augmenting exponentially. Despite the great efforts to find a cure, current treatments remain ineffective or have low efficacy. Increasing lines of evidence point to exacerbated oxidative stress, mitochondrial dysfunction and chronic neuroinflammation as common pathological mechanisms underlying neurodegeneration. We will address the role of the nuclear factor E2-related factor 2 (Nrf2) as a potential target for the treatment of NDDs. The Nrf2–ARE pathway is an intrinsic mechanism of defence against oxidative stress. Nrf2 is a transcription factor that induces the expression of a great number of cytoprotective and detoxificant genes. There are many evidences that highlight the protective role of the Nrf2–ARE pathway in neurodegenerative conditions, as it reduces oxidative stress and neuroinflammation. Therefore, the Nrf2 pathway is being increasingly considered a therapeutic target for NDDs. Herein we will review the deregulation of the Nrf2 pathway in different NDDs and the recent studies with Nrf2 inducers as “proof-of-concept” for the treatment of those devastating pathologies.
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, Manuela
Subchronic 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.
Melatonin–sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a ‘drug–prodrug’ mechanism of action
(British Journal of Pharmacology, 2015) Egea, Javier; Buendia, Izaskun; Parada, Esther; Navarro González De Mesa, Elisa; Rada, Patricia; Cuadrado, Antonio; López, Manuela G.; García García, Antonio; León Martínez, Rafael
Background and purpose: Neurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties. Experimental approach: Compound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia. Key results: ITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production. Conclusion and implications: ITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases.