Ana I. Casas
Maastricht University
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Publication
Featured researches published by Ana I. Casas.
Antioxidants & Redox Signaling | 2015
Ana I. Casas; V Thao-Vi Dao; Andreas Daiber; Ghassan J. Maghzal; Fabio Di Lisa; Nina Kaludercic; Sonia Leach; Antonio Cuadrado; Vincent Jaquet; Tamara Seredenina; Karl Heinz Krause; Manuela G. López; Roland Stocker; Pietro Ghezzi; Harald Schmidt
Abstract Significance: Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. Recent Advances: We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. Critical Issues: Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. Future Directions: Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171–1185.
Antioxidants & Redox Signaling | 2015
V Thao-Vi Dao; Ana I. Casas; Ghassan J. Maghzal; Tamara Seredenina; Nina Kaludercic; Natalia Robledinos-Antón; Fabio Di Lisa; Roland Stocker; Pietro Ghezzi; Vincent Jaquet; Antonio Cuadrado; Harald Schmidt
Abstract Significance: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. Critical Issues: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. Future Directions: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. Antioxid. Redox Signal. 23, 1113–1129.
Clinica Chimica Acta | 2016
Aneta Wojnicz; José Avendaño Ortiz; Ana I. Casas; Andiara E. Freitas; Manuela G. López; Ana Ruiz-Nuño
Analysis of neurotransmitters and their metabolites is useful for the diagnosis of central nervous system diseases. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with protein precipitation was developed to monitor levels of adrenaline (AD), noradrenaline (NA), glutamic acid (Glu), γ-aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in rat brain tissue. Isoprenaline was used as an internal standard (IS). Neurotransmitters and metabolites were eluted with a reverse phase column under gradient conditions through a mobile phase consisting of 0.2% formic acid water solution/acetonitrile. The compounds were detected and quantified by LC-MS/MS with positive or negative electrospray ionization, which operates in multiple-reaction monitoring mode. The method was linear or polynomial (R(2)>0.99) for AD, NA, Glu, GABA, DA, 5-HT, 5-HIAA, and MHPG in the range of 0.25-200, 0.5-200, 250-20,000, 250-20,000, 0.25-200, 10-3000, 1-50, and 1-50ng/mL, respectively. The validation assays for accuracy and precision, matrix effect, extraction recovery, stability and carry-over of the samples for neurotransmitters and metabolites were consistent with the requirements of regulatory agencies. The method enables rapid quantification of neurotransmitters and their metabolites and has been applied in the nuclear factor (erythroid 2-derived)-like 2 (Nrf2) knockout mouse model of depression.
Clinical Pharmacology & Therapeutics | 2016
J.M. Oettrich; Vu Thao-Vi Dao; J. Frijhoff; Pamela W. M. Kleikers; Ana I. Casas; Adrian J. Hobbs; Harald Schmidt
Therapies that modulate cyclic guanosine‐3′‐5′‐monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMPs relevance is likely to go beyond this rather limited organ‐based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof‐of‐concept of network pharmacology.
Journal of Cerebral Blood Flow and Metabolism | 2016
Christoph Kleinschnitz; Stine Mencl; Pamela W. M. Kleikers; Michael K. Schuhmann; Manuela G. López; Ana I. Casas; Bilge Surun; Andreas Reif; Harald Schmidt
Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor–post-synaptic density protein-95–neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1−/− mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.
Proceedings of the National Academy of Sciences of the United States of America | 2017
Ana I. Casas; Eva Geuss; Pamela W. M. Kleikers; Stine Mencl; Alexander M. Herrmann; Izaskun Buendia; Javier Egea; Sven G. Meuth; Manuela G. López; Christoph Kleinschnitz; Harald Schmidt
Significance Why the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke. Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood–brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke.
Data in Brief | 2016
Aneta Wojnicz; José Avendaño Ortiz; Ana I. Casas; Andiara E. Freitas; Manuela G. López; Ana Ruiz-Nuño
The data presented in this article supports the rat brain sample preparation procedure previous to its injection into the liquid chromatography–tandem mass spectrometry (LC–MS/MS) system to monitor levels of adrenaline, noradrenaline, glutamic acid, γ-aminobutyric acid, dopamine, 5-hydroxytryptamine, 5-hydroxyindole acetic acid, and 3-methoxy-4-hydroxyphenylglycol. In addition, we describe the method validation assays (such as calibration curve, lower limit of quantification, precision and accuracy intra- and inter-day, selectivity, extraction recovery and matrix effect, stability, and carry-over effect) according to the United States Food and Drug Administration and European Medicine Agency to measure in one step different neurotransmitters and their metabolites. The data supplied in this article is related to the research study entitled: “Simultaneous determination of 8 neurotransmitters and their metabolite levels in rat brain using liquid chromatography in tandem with mass spectrometry: application to the murine Nrf2 model of depression” (Wojnicz et al. 2016) [1].
BMC Clinical Pharmacology | 2015
Ana I. Casas; Friederike Langhauser; Vu Thao-Vi Dao; Emre Guney; Pamela W. M. Kleikers; Manuela G. López; Jörg Menche; Albert-László Barabási; Christoph Kleinschnitz; Harald Schmidt
Based on non-hypothesis-driven approaches genetic evidence suggests that diseases are interrelated differently to our current organ-based ontology. In fact, common effector mechanisms, when affected or triggered seem to produce pathophenotypes in diverse organs or co-morbidities. This will lead eventually to a revised disease nomenclature and opens up entirely new approaches for diagnosis and treatment. In this context, we noted that a common cardiovascular target, the cGMP-forming Fe(II) haem protein, soluble guanylate cyclase (sGC), appears to be situated in a common mechanism network that is prominently relevant to stroke. Ischemic stroke is the second leading cause of death worldwide and the leading cause of disability. Despite this high medical need only a single drug is available but due to its limited time window and risk of bleeding 85% of all patients are excluded from treatment. As a possible add-on, vasoactive drugs however typically dilate normal blood vessels and cause a paradoxical “steal phenomenon” by both shunting blood to healthy vascular beds and a systemic blood pressure drop. Upon middle cerebral artery occlusion sGC protein and nitric oxide-stimulated activity in the ischemic hemisphere were dramatically down-regulated leading to a high proportion of oxidized and/or haem-free apo-sGC activity. Pharmacological targeting of apo-sGC in vitro under oxygen and glucose deprivation conveyed strong neuroprotection via ERK/CREB signalling. In vivo, post-stroke apo-sGC activation by two distinct members of this compound class augmented cerebral blood-flow whilst leaving systemic blood pressure unaffected, reduced infarct size and increased survival. Different apo-sGC activators are in advanced stages of clinical development for different cardiovascular indications. Systems biology and network medicine and our preliminary target validation suggest that they should be urgently tested for repurposing as first-in-class, mechanism-based neuroprotective drugs in stroke.
npj Systems Biology and Applications | 2018
Friederike Langhauser; Ana I. Casas; Vu-Thao-Vi Dao; Emre Guney; Jörg Menche; Eva Geuss; Pamela W. M. Kleikers; Manuela G. López; Albert-L. Barabási; Christoph Kleinschnitz; Harald Schmidt
Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.Systems based pharmacology: drug repurposing by diseasomeSystems medicine utilizes common genetic origins and co-morbidities to uncover mechanistic links between diseases, which are summarized in the diseasome. Shared pathomechanisms may also allow for drug repurposing within these disease clusters. Here, Schmidt and co-workers show indeed that, based on this principle, a cardio-pulmonary drug can be surprisingly repurposed for a previously not recognised application as a direct neuroprotectant. They find that the cyclic GMP forming soluble guanylate cyclase becomes dysfunctional upon stroke but regains catalytic activity in the presence of specific activator compounds. This new mechanism-based therapy should be urgently validated clinically as a possible first-in-class treatment in stroke.
bioRxiv | 2018
Thao-Vi Dao; Sebastian Altenhöfer; Mahmoud H. Elbatreek; Ana I. Casas; Peter Lijnen; Merlijn J. Meens; Ulla G. Knaus; Harald Schmidt
Unphysiological reactive oxygen species (ROS) formation is considered an important pathomechanism for several diseasephenotypes with high unmet medical need. After the clinical failure of antioxidants, inhibition of disease-relevant enzymatic sources of ROS appears to be the most promising alternative approach. With respect to most promising drug target, NADPH oxidases (NOXs) stand out, however, validation has been restricted mainly to genetically modified mice. Validation in other species including human is lacking and it is unclear whether the different NOX isoforms are sufficiently distinct for selective pharmacological inhibition. Here we show for the five most advanced NOX inhibitors that pharmacological isoform selectivity can be achieved. NOX1 was most potently (IC50) targeted by ML171 (0.1 μM); NOX2, by VAS2870 (0.7 μM); NOX4, by M13 (0.01 μM) and NOX5, by ML090 (0.01 μM). Of note, previously unrecognised non-specific antioxidant and assay artefacts may limit interpretations in some systems, which included, surprisingly, the clinically most advanced compound, GKT136901. As proof-of-principle for our pharmacological target validation approach, we used a human blood-brain barrier model and our NOX inhibitor panel at IC50 concentrations. Indeed, the protective efficacy pattern of this compound panel pointed towards a functional role NOX4 confirming previous genetic targeting. These findings strongly encourage further lead optimisation efforts for isoform-selective NOX inhibitors and their clinical development and provide already now an experimental alternative when genetic targeting of NOXs is not an option.