Person: León Martínez, Rafael
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First Name
Rafael
Last Name
León Martínez
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Orgánica
Identifiers
9 results
Search Results
Now showing 1 - 9 of 9
Item ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia(ACS Chemical Neuroscience, 2016) Buendia, Izaskun; Tenti, Giammarco; Michalska Dziama, Patrycja; Méndez-López, Iago; Luengo, Enrique; Satriani, Michele; Padín-Nogueira, Fernando; López, Manuela G.; Ramos García, María Teresa; García, Antonio G.; Menéndez Ramos, José Carlos; León Martínez, RafaelDuring brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.Item Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease(Scientific Reports, 2017) Gameiro, Isabel; Michalska Dziama, Patrycja; Tenti, Giammarco; Cores Esperón, Ángel; Buendia, Izaskun; Rojo, Ana I.; Georgakopoulos, Nikolaos D.; López, Manuela G.; Hernández, Jesús M.; Ramos García, María Teresa; Wells, Geoffrey; Cuadrado, Antonio; Menéndez Ramos, José Carlos; León Martínez, RafaelThe formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.Item The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities(Journal of Neurochemistry, 2018) Martín De Saavedra Álvarez De Uribarri, María Dolores; Navarro, Elisa; Moreno‐Ortega, Ana J.; Cunha,, Mauricio P.; Buendia, Izaskun; Hernansanz‐Agustín, Pablo; León Martínez, Rafael; Cano‐Abad,, María F.; Martínez‐Ruiz, Antonio; Martínez‐Murillo, Ricardo; Duchen, Michael R.; López, Manuela G.Growing evidence suggests a close relationship between Alzheimer′s Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE/PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE/PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+]c) were potentiated in the APPSWE/PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE/PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.Item Pharmacological doses of melatonin impede cognitive decline in tau-related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux(Journal of Pineal Research, 2019) Luengo, Enrique; Buendia, Izaskun; Fernández-Mendívil, Cristina; Negredo, Pilar; Michalska Dziama, Patrycja; Hernández-García, Borja; Sánchez-Ramos, Cristina; Bernal, Juan A.; Ikezu, Tsuneya; López, Manuela G.; León Martínez, RafaelAlterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV-hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau-related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV-hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase-3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.Item 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, RafaelNeurodegenerative 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.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 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.Item 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, RafaelBackground 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.