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Simon D.,Autonomous University of Madrid | Medina M.,NOSCIRA | Avila J.,Autonomous University of Madrid | Wandosell F.,Autonomous University of Madrid
CNS and Neurological Disorders - Drug Targets | Year: 2011

Few targets for neuroprotection have been defined in Alzheimer's disease (AD). Recent data from the role of Wnt, insulin-like growth factor-1 and estradiol pathways in AD suggest some therapeutic targets for disease treatment, and have led us to evaluate the "common factors" in these pathways as further candidate targets. These data have led us to propose that glycogen synthase kinase-3 (GSK-3) inhibition appears to be a common feature of these pathways. Besides, considering that GSK-3 activation seems to be correlated with neurodegeneration, its selection as a relevant target appears obvious. The capacity of different GSK-3 inhibitors to prevent amyloid β-peptide neurotoxicity and tau phosphorylation has been evaluated in order to develop novel clinical and therapeutic approaches. Different approaches could be used to search for new neuroprotective compounds. The most classical of these is to first define the target and then design a specific in vitro screening assay for it. Alternatively, a cell model of cell culture could be used as a "primary screen". Following this rationale, we have used a combined approach in which we first used an in vitro system to select compounds able to inhibit recombinant GSK3β. Subsequently, we subjected the candidate compounds to three consecutive cell-based complementary screening assays. First, cell viability was assessed using a neuroblastoma cell line before assaying the capacity of the compounds to reduce tau phosphorylation. Finally, we designed a neuronal cell model of apoptosis using the phosphatidylinositol kinase-3 inhibitor LY294002. Finally, we summarize several new compounds with "neuroprotective" properties. © 2011 Bentham Science Publishers.

Serrano A.,Hospital Regional Universitario Carlos Haya | Serrano A.,Institute Salud Carlos III | Pavon F.J.,Hospital Regional Universitario Carlos Haya | Pavon F.J.,Institute Salud Carlos III | And 17 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

Enhancement of adi-ponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponec-tin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance. © 2012 the American Physiological Society.

Monte F.L.,TU Darmstadt | Kramer T.,TU Darmstadt | Bolander A.,TU Darmstadt | Plotkin B.,Tel Aviv University | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC 50 = 140 nM) and the pyridylurea 62 (IC 50 = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC 50 = 330 nM) in our assays. © 2011 Elsevier Ltd. All rights reserved.

Trueba-Saiz A.,Cajal Institute CSIC | Trueba-Saiz A.,CIBER ISCIII | Cavada C.,Metropolitan Autonomous University | Fernandez A.M.,Cajal Institute CSIC | And 12 more authors.
Translational Psychiatry | Year: 2013

Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients.

Maes M.,Maes Clinics at TRIA | Fisar Z.,Charles University | Medina M.,Noscira | Scapagnini G.,University of Molise | And 3 more authors.
Inflammopharmacology | Year: 2012

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cyto-kines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy. © 2011 CARS.

Noscira and Neuropharma | Date: 2010-03-30

Chemicals used in industry and science. Pharmaceutical preparations, in particular preparations for the treatment of neuron and central nervous system diseases, sanitary preparations for medical purposes; dietetic products for medical purposes in the nature of dietetic foods adapted for medical use. Business operation, business management, business marketing for the goods and services in the medical, pharmaceutical, parapharmaceutical, nutrition, perfumery, hygiene and oral care fields; advertising, business management and business administration. Scientific and technological services, namely, scientific research and technological consultation in the technology field of medical equipment and pharmaceutical products; scientific and technology research in the fields of medicine and pharmaceuticals. Medical assistance; medical information on the internet; medical information about pharmaceuticals.

Noscira and Neuropharma | Date: 2010-07-13

Chemicals used in industry and science. [ Pharmaceutical preparations, in particular preparation for the treatment of neuron and central nervous system diseases, sanitary preparations for medical purposes; dietetic products for medical purposes in the nature of dietetic foods adapted for medical use ]. Scientific and technological services, namely, consulting services in the fields of medicine and pharmaceuticals; scientific and technology research in the fields of medicine and pharmaceuticals.

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