INTERACCION ENTRE LA NEUROINFLAMACION, EL ESTRES OXIDATIVO Y LOS MECANISMOS PROTEOSTATICOS: NUEVAS DIANAS PARA PREVENIR LA NEURODEGENERACION EN EA

RTI2018-095793-B-I00

Nombre agencia financiadora Agencia Estatal de Investigación
Acrónimo agencia financiadora AEI
Programa Programa Estatal de I+D+i Orientada a los Retos de la Sociedad
Subprograma Programa Estatal de I+D+i Orientada a los Retos de la Sociedad
Convocatoria Retos Investigación: Proyectos I+D+i
Año convocatoria 2018
Unidad de gestión Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020
Centro beneficiario UNIVERSIDAD AUTONOMA DE MADRID
Identificador persistente http://dx.doi.org/10.13039/501100011033

Publicaciones

Found(s) 5 result(s)
Found(s) 1 page(s)

1-(2′,5′-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (RGM079): A positive allosteric modulator of α7 nicotinic receptors with analgesic and neuroprotective activity

Digital.CSIC. Repositorio Institucional del CSIC
  • Pérez de Vega, M. Jesús
  • Fernández-Mendívil, Cristina
  • Torre Martínez, R. de la
  • González-Rodríguez, Sara
  • Mulet Soler, José
  • Sala, Francisco
  • Sala, Salvador
  • Criado, Manuel
  • Moreno-Fernández, Silvia
  • Miguel, Marta
  • Fernández-Carvajal, Asia
  • Ferrer-Montiel, Antonio
  • López, Manuela G.
  • González-Muñiz, Rosario
Acetylcholine α7 nicotinic receptors are widely expressed in the brain, where they are involved in the central processing of pain as well as in neuropsychiatric, neurodegenerative, and inflammatory processes. Positive allosteric modulators (PAMs) show the advantage of allowing the selective regulation of different subtypes of acetylcholine receptors without directly interacting with the agonist binding site. Here, we report the preparation and biological activity of a fluoro-containing compound, 1-(2′,5′-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (8, RGM079), that behaves as a potent PAM of the α7 receptors and has a balanced pharmacokinetic profile and antioxidant properties comparable or even higher than well-known natural polyphenols. In addition, compound RGM079 shows neuroprotective properties in Alzheimer's disease (AD)-toxicity related models. Thus, it causes a concentration-dependent neuroprotective effect against the toxicity induced by okadaic acid (OA) in the human neuroblastoma cell line SH-SY5Y. Similarly, in primary cultures of rat cortical neurons, RGM079 is able to restore the cellular viability after exposure to OA and amyloid peptide Aβ, with cell death almost completely prevented at 10 and 30 μM, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the complete Freund's adjuvant (CFA)-induced paw inflammation model after intraperitoneal administration., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER) grant number SAF2015-66275-C2-R and RTI2018-097189-C2 to RGM and AFM, and RTI2018-095793-B-I00 to MGL, the Comunidad de Madrid/European Union Ref S2017/BMD-3827 to MGL and the CSIC, grant number 201980E030 to RGM.




Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties

Digital.CSIC. Repositorio Institucional del CSIC
  • Herrera-Arozamena, Clara
  • Estrada-Valencia, M.
  • Pérez, Concepción
  • Lagartera, Laura
  • Morales-García, José A.
  • Perez-Castillo, Ana
  • Franco-Gonzalez, Juan Felipe
  • Michalska, Patrycja
  • Duarte, Pablo
  • León, Rafael
  • López, Manuela G.
  • Mills, Alberto
  • Gago, Federico
  • García-Yagüe, Ángel Juan
  • Fernández-Ginés, Raquel
  • Cuadrado, Antonio
  • Rodríguez-Franco, María Isabel
New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MTR and MTR, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and co-planarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MTR and MTR, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours., The authors gratefully acknowledge the following financial
supports: Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grants RTI2018-093955-B-C21 and SAF2015-64948-C2-1-R to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L., SAF2015-64629-C2-2-R to F.G.), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 e NRF24ADCM), Health Institute Carlos III (Miguel Servet II ProgramCP16/00014 and grant PI17/01700 to R.L.).
CH-A and P.M. thank their PhD fellowships from Spanish Ministry of Education (MEC, PhD grant FPU16/01704 and mobility grant FPUEST17/00233 to CH-A and FPU13/03737 to P.M.).




Melatonin-sulforaphane hybrid ITH12674 attenuates glial response in vivo by blocking LPS binding to MD2 and receptor oligomerization

Digital.CSIC. Repositorio Institucional del CSIC
  • Michalska, Patrycja
  • Buendía Abaitua, Izaskun
  • Duarte, Pablo
  • Fernández-Mendívil, Cristina
  • Negredo, Pilar
  • Cuadrado, Antonio
  • López, Manuela G.
  • León, Rafael
Neuroinflammation is increasingly associated to the onset and progression of neurodegenerative diseases. Furthermore, several lines of evidence have demonstrated the capacity of aberrant protein aggregates to activate the immune response, accelerating the advance of the disease. Compound ITH12674 is a melatonin-sulforaphane hybrid designed to exert a dual drug-prodrug mechanism of action that combines potent NRF2 induction and free radical scavenger activity. ITH12674 also showed neuroprotective properties in oxidative stress related models, that were dependant on its NRF2 inducing properties. Given the high impact of neuroinflammation in the pathogenesis of neurodegeneration, we foresaw to study the anti-inflammatory properties of ITH12674. ITH12674 reduced inflammatory markers in glial cell cultures and hippocampal tissue after LPS administration. The anti-inflammatory effect was related to inhibition of TLR4 receptors due to a direct interaction with the TLR4/MD2 complex at the hydrophobic cavity of MD2. ITH12674 is endowed with anti-inflammatory properties, that are complementary to the NRF2 inducing activity and neuroprotective properties. Thus, ITH12674 could be of potential interest for the treatment of diseases with chronic neuroinflammation., This work was supported by grants from IS Carlos III co-financed by the European Regional Development’s funds (FEDER), Programa Miguel Servet II (CP16/00014) and research project (grant PI17/01700) to RL; Fundación La Caixa, CaixaImpulse program (grant CI17-00048) to RL; Comunidad Autónoma de Madrid (grant B2017/BMD-3827) and Spanish Ministry of Science, Innovation and Education (grant RTI2018-095793-B-I00) to MGL. P.M., P.D. and C.F.-M thanks MECD for FPU fellowships (13/0373716/03977 and 15/03269 respectively). I.B thanks MECD for Juan de la Cierva fellowship (FJCI-2016/28282). We would also like to thank “Fundación Teófilo Hernando” for its continued support., Peer reviewed




Na+ controls hypoxic signalling by the mitochondrial respiratory chain

Digital.CSIC. Repositorio Institucional del CSIC
  • Hernansanz-Agustín, Pablo
  • Choya-Foces, Carmen
  • Carregal-Romero, Susana
  • Ramos, Elena
  • Oliva, Tamara
  • Villa-Piña, Tamara
  • Moreno, Laura
  • Izquierdo-Álvarez, Alicia
  • Cabrera-García, J. Daniel
  • Cortés, Ana
  • Lechuga-Vieco, Ana V.
  • Jadiya, Pooja
  • Navarro, Elena
  • Parada, Esther
  • Palomino-Antolín, Alejandra
  • Tello, Daniel
  • Acín-Pérez, Rebeca
  • Rodríguez-Aguilera, Juan Carlos
  • Navas, Plácido
  • Cogolludo, Angel
  • López-Montero, Iván
  • Martínez-del-Pozo, Álvaro
  • Egea, Javier
  • López, Manuela G.
  • Elrod, John W.
  • Ruiz-Cabello, Jesús
  • Bogdanova, Anna
  • Enríquez, José Antonio
  • Martínez-Ruiz, Antonio
All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1,2,3,4, a phenomenon that occurs in hypoxia4,5,6,7,8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism., This research has been financed by Spanish Government grants (ISCIII and AEI agencies, partially funded by the European Union FEDER/ERDF) CSD2007-00020 (RosasNet, Consolider-Ingenio 2010 programme to A.M.-R. and J.A.E.); CP07/00143, PS09/00101, PI12/00875, PI15/00107 and RTI2018-094203-B-I00 (to A.M.-R.); CP12/03304 and PI15/01100 (to L.M.); CP14/00008, CPII19/00005 and PI16/00735 (to J.E.); SAF2016-77222-R (to A. Cogolludo); PI17/01286 (to P.N.); SAF2015-65633-R, RTI2018-099357-B-I00 and CB16/10/00282 (to J.A.E.); RTI2018-095793-B-I00 (to M.G.L.); and SAF2017-84494-2-R (to J.R.-C.), by the European Union (ITN GA317433 to J.A.E. and MC-CIG GA304217 to R.A.-P.), by grants from the Comunidad de Madrid B2017/BMD-3727 (to A. Cogolludo) and B2017/BMD-3827 (to M.G.L.), by a grant from the Fundación Domingo Martínez (to M.G.L. and A.M.-R.), by the Human Frontier Science Program grant HFSP-RGP0016/2018 (to J.A.E.), by grants from the Fundación BBVA (to R.A.-P. and J.R.-C.), by the UCM-Banco Santander grant PR75/18-21561 (to A.M.-d.-P.), by the Programa Red Guipuzcoana de Ciencia, Tecnología e Información 2018-CIEN-000058-01 (to J.R.-C.) and from the Basque Government under the ELKARTEK Program (grant no. KK-2019/bmG19 to J.R.-C.), by the Swiss National Science Foundation (SNF) grant 310030_124970/1 (to A.B.), by a travel grant from the IIS-IP (to P.H.-A.) and by the COST actions TD0901 (HypoxiaNet) and BM1203 (EU-ROS). The CNIC is supported by the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (Spanish Government award SEV-2015-0505). CIC biomaGUNE is supported by the María de Maeztu Units of Excellence Program from the Spanish Government (MDM-2017-0720). P.H.-A. was a recipient of a predoctoral FPU fellowship from the Spanish Government. E.N. is a recipient of a predoctoral FPI fellowship from the Universidad Autónoma de Madrid (UAM). A.M.-R., L.M. and J.E. are supported by the I3SNS or ‘Miguel Servet’ programmes (ISCIII, Spanish Government; partially funded by the FEDER/ERDF)., Peer reviewed




Evaluation of compound NF1086, a NRF2 inducer-melatonin derivative, in a tauopathy model

Digital.CSIC. Repositorio Institucional del CSIC
  • Sastre, E. del
  • Fernández-Mendivil, C.
  • Luengo, E.
  • Trigo-Alonso, P.
  • Viqueira, L.
  • Domínguez, J.
  • Cuadrado, A.
  • Rodríguez-Franco, María Isabel
  • López, M. G.
This study has been developed within a multidisciplinary project designed
to search for multitarget compounds with NRF2 inducing capacity, by inhibiting
the Keap1-NRF2 interaction, for the treatment of Alzheimer¿s disease. We have
focused on melatonin derivatives, which additionally induce the NRF2 transcription
factor, master regulator of oxidative stress. NF1086 is a melatonin derivative
which duplicates NRF2 expression at a concentration below 1 ¿M, has antioxidant
properties and is predicted to cross the BBB through the PAMPA test. Further on,
in vivo target validation was assessed by measuring NRF2 and some of its target
genes in brain samples after peripheral administration.
To test the potential effects of NF1086 in tauopathy, primary cortical neuronal
cultures were treated with adeno-associated particles which express the human tau
protein with P301L mutation (AAV-hTauP301L). In this in vitro model, phosphorylated
tau was signi¿¿cantly reduced in cultures treated with NF1086. We next evaluated if
the compound could provide neuroprotective effects in vivo. Tauopathy in adult (3-4
months) C57BL/6J mice was generated by injecting stereotaxically AAV-hTauP301L
in both hippocampi; mice were treated with 20 or 50 mg/Kg/day orally for 35 days,
starting after the tauopathy induction. NF1086 treatment prevented cognitive decline
promoted by tauopathy. Moreover, it reduced tau hyperphosphorylated protein in
different brain regions and reduced neuroin¿¿ammation. Interestingly, similar results
were achieved in aged 20 months old mice.
In conclusion, NF1086 is a melatonin derivative that induces NRF2 with
neuroprotective properties with potential therapeutic interest in tauopathy and related
NDDs; however, future studies need to be conducted to elucidate its mechanism of
action.
Acknowledgments. The Comunidad Autónoma de Madrid (grant B2017/BMD-3827), the
Universidad Autónoma de Madrid, the Ministerio de Economía y Competencia (RTI2018-
095793-B-I00) and the Ministerio de Ciencia, Innovación y Universidades (FPU18/00630)
for supporting this work.