Person: Michalska Dziama, Patrycja
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First Name
Patrycja
Last Name
Michalska Dziama
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Identifiers
5 results
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Item Novel Multitarget Hybrid Compounds for the Treatment of Alzheimer’s Disease(Current Topics in Medicinal Chemistry, 2016) Michalska Dziama, Patrycja; Buendia, Izaskun; Almale Del Barrio, Laura; León Martínez, RafaelAlzheimer's disease (AD) is the most prevalent among the aging diseases known as neurodegenerative disorders. Drug design programs over the last two decades were mainly based on the cholinergic, the amyloid or the tau hypothesis. However, none of the new drugs have a real impact on the outcome of the disease. The complex nature of AD has led to new approaches for drug development programs, the multitarget drug design hypothesis. Based on this hypothesis, the generation of multitarget hybrid compounds from previously known active molecules has been one of the most widely used to obtain new candidates for the future treatment of AD. Here, we summarize recent developments based on the hybridization hypothesis to obtain a potential clinical candidate for AD.Item Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models(Neuropharmacology, 2015) Buendia Abaitua, Izaskun; Gómez Rangel, Vanessa; Gónzalez Lafuente, Laura; Parada Pérez, Esther; León Martínez, Rafael; Gameiro Ros, Isabel Marina; Michalska Dziama, Patrycja; Laudon, Moshe; Egea Máiquez, Francisco Javier; García López, ManuelaStopping the ischemic cascade by targeting its components is a potential strategy for acute ischemic stroke treatment. During ischemia and especially over reperfusion, oxidative stress plays a major role in causing neuronal cell death. Melatonin has been previously reported to provide neuroprotective effects in in vivo models of stroke by a mechanism that implicates melatonin receptors. In this context, this study was planned to test the potential neuroprotective effects of the novel melatonin MT1/MT2 receptor agonist, Neu-P11, against brain ischemia in in vitro and in vivo models, and to elucidate its underlying mechanism of action. Neu-P11 proved to be a good antioxidant, to protect against glutamate-induced excitotoxicity and oxygen and glucose deprivation in hippocampal slices, and to reduce infarct volume in an in vivo stroke model. Regarding its mechanism of action, the protective effect of Neu-P11 was reverted by luzindole (melatonin receptor antagonist), AG490 (JAK2 inhibitor), LY294002 (PI3/AKT inhibitor) and PD98059 (MEK/ERK1/2 inhibitor). In conclusion, Neu-P11 affords neuroprotection against brain ischemia in in vitro and in vivo models by activating a pro-survival signaling pathway that involves melatonin receptors, JAK/STAT, PI3K/Akt and MEK/ERK1/2.Item Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease(Antioxidants, 2020) Michalska Dziama, Patrycja; Mayo, Paloma; Fernández-Mendívil, Cristina; Tenti, Giammarco; Duarte, Pablo; Buendia, Izaskun; Ramos García, María Teresa; López, Manuela G.; Menéndez Ramos, José Carlos; León, Rafael; León Martínez, RafaelAlzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca2+ homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3–b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.Item 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, RafaelNeurodegenerative 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.Item Inclusion complex of ITH12674 with2-hydroxypropyl-beta-cyclodextrin: Preparation, physical characterization and pharmacological effect(Carbohydrate Polymers, 2016) Michalska Dziama, Patrycja; Wojnicz, Aneta; Ruiz-Nuño, Ana; Abril, Sheila; Buendia, Izaskun; León Martínez, RafaelITH12674 is a multitarget drug, designed to exert a dual “drug-prodrug” mechanism of action, able toinduce the phase II antioxidant and anti-inflammatory response for the treatment of brain ischemia.However, its physicochemical properties limit its potential preclinical development due to its low watersolubility and instability towards heat and pH variations. In order to improve its properties, we preparedthe inclusion complex of ITH12674 with 2-hydroxypropyl- -cyclodextrin (HP- -CD) by the freeze-drying method. The formation of the inclusion complex was confirmed by FT-IR spectroscopy, PXRD,DSC,1H NMR and SEM techniques. Experimental results showed that the inclusion complex enhanced itswater solubility and stability against heat, acidic and basic conditions. Furthermore, the inclusion com-plex, prepared in water solution, exerted the same potency to induce the phase II antioxidant response asthe pure ITH12674. Thus the formation of the inclusion complex with HP- -CD is a very effective methodto stabilize and solubilize the active compound for its future preclinical development.