Javier Egea, PhD. Miguel Servet Researcher Member of Instituto Teófilo Hernando for Drug Discovery Universidad Autónoma de Madrid, Madrid, Spain

Transcription

1 Javier Egea, PhD Miguel Servet Researcher Member of Instituto Teófilo Hernando for Drug Discovery Universidad Autónoma de Madrid, Madrid, Spain RESEARCH INTEREST We are interested in the role of microglia in the healthy and diseased brain, and studying microglia based therapeutics for different disorders including Stroke, Traumatic Brain Injury, and other brain diseases (AD). (1) Microglial function in the Healthy Brain Microglia are the primary immune cells of the CNS, and are highly similar to peripheral macrophages. They act as the major inflammatory cell type in the brain, and respond to pathogens or damage associated molecular pattern molecules (PAMPs/DAMPs). DAMPs are cell derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. These hazardous signals polarize microglia toward a classical pro inflammatory phenotype termed M1 rapidly change morphology, proliferate and migrate to the site of infection/injury where they phagocytose and destroy pathogens as well as remove damaged cells. M1 microglia release highly pro inflammatory cytokines (TNF, IL 1, IL 6, IL 12, and IL 23) as well as chemokines, prostaglandins, NO and reactive oxygen species, which help to elevate and direct the immune response. The pro inflammatory polarization of microglia is often followed by a long lasting repair stage known as the alternative or M2 phase in which microglia display hypertrophic cell bodies with thick and ramified processes and high phagocytic capacity. M2 microglia is crucial in the resolution of the inflammatory response, through the production of anti inflammatory cytokines such as IL 10. Microglia have also been extensively studied for their harmful roles in neurodegenerative diseases and brain injuries, such as Alzheimer s disease, Parkinson s disease, ischemic injury, and traumatic brain injuries. (2) Mechanisms involved in the resolution of the inflammation in stroke. Alternative activated microglia (M2) are critical to the resolution of inflammation. We are interested in the actions of different molecules (nicotinic agonists, TLR4 antagonists ) on these microglia and the basic mechanisms by which microglia switch from pro inflammatory to anti inflammatory phenotypes. We find that microglial α7 nachrs are key players promoting 1

2 inflammatory resolution in ischemia. Now, we are exploring new therapeutic targets implicated in the resolution of inflammation in brain ischemia. (3) Research focus for the next five years. During the next 5 years I will focus on the understanding of inflammasome activation by released dangers signals of death neurons in ischemia. This concept of danger signals activating the immune system could be the origin of the complex cytokine network that orchestrates the inflammatory response. RECENT PUBLICATIONS 2010 PARADA E*, EGEA J*, ROMERO A, DEL BARRIO L, GARCÍA AG, LÓPEZ MG. Poststress treatment with PNU can rescue SH SY5Y cells undergoing apoptosis via α7 nicotinic receptors linked to a Jak2/Akt/HO 1 signaling pathway. Free Radic Biol Med. 49: NICOLAU SM, EGEA J, LÓPEZ MG, GARCÍA AG. Mitochondrial Na+/Ca2+ exchanger, a new target for neuroprotection in rat hippocampal slices. Biochem Biophys Res Commun. 400: DE LOS RÍOS C, EGEA J, MARCO CONTELLES J, LEÓN R, SAMADI A, IRIEPA I, MORALEDA I, GÁLVEZ E, GARCÍA AG, LÓPEZ MG, VILLARROYA M, ROMERO A. Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8 naphthyridine derivatives. J Med Chem. 53: ROMERO A*, EGEA J*, GARCÍA AG, LÓPEZ MG. Synergistic neuroprotective effect of combined low concentrations of galantamine and melatonin against oxidative stress in SH SY5Y neuroblastoma cells. J Pineal Res. 49: EGEA J, GARCÍA AG, VERGES J, MONTELL E, LÓPEZ MG. Antioxidant, antiinflammatory and neuroprotective actions of chondroitin sulfate and proteoglycans. Osteoarthritis Cartilage. 18 Suppl 1:S EGEA J, DE LOS RIOS C. 1,8 Naphthyridine derivatives as cholinesterases inhibitors and cell Ca2+ regulators, a multitarget strategy for Alzheimer's disease. Curr Top Med Chem. 11: MARTINS C, CARREIRAS MC, LEÓN R, DE LOS RÍOS C, BARTOLINI M, ANDRISANO V, IRIEPA I, MORALEDA I, GÁLVEZ E, LÓPEZ MG, EGEA J, SAMADI A, CHIOUA M, MARCO CONTELLES J. Synthesis and biological assessment of diversely substituted furo[2,3 2

3 b]quinolin 4 amine and pyrrolo[2,3 b]quinolin 4 amine derivatives, as novel tacrine analogues. Eur J Med Chem. 46: BARTOLINI M, PISTOLOZZI M, ANDRISANO V, EGEA J, LÓPEZ MG, IRIEPA I, MORALEDA I, GÁLVEZ E, MARCO CONTELLES J, SAMADI A. Chemical and pharmacological studies on enantiomerically pure p methoxytacripyrines, promising multi target directed ligands for the treatment of Alzheimer's disease. ChemMedChem. 6: DEL BARRIO L, MARTÍN DE SAAVEDRA MD, ROMERO A, PARADA E, EGEA J, AVILA J, MCINTOSH JM, WONNACOTT S, LÓPEZ MG. Neurotoxicity induced by okadaic acid in the human neuroblastoma SH SY5Y line can be differentially prevented by α7 and β2* nicotinic stimulation. Toxicol Sci. 123: MOLZ S, DAL CIM T, BUDNI J, MARTÍN DE SAAVEDRA MD, EGEA J, ROMERO A, DEL BARRIO L, RODRIGUES AL, LÓPEZ MG, TASCA CI. Neuroprotective effect of guanosine against glutamate induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol 3 kinase/akt/ glycogen synthase kinase 3β pathway activation and inducible nitric oxide synthase inhibition. J Neurosci Res. 89: BUDNI J, ROMERO A, MOLZ S, MARTÍN DE SAAVEDRA MD, EGEA J, DEL BARRIO L, TASCA CI, RODRIGUES AL, LÓPEZ MG. Neurotoxicity induced by dexamethasone in the human neuroblastoma SH SY5Y cell line can be prevented by folic acid. Neuroscience. 190: GONZÁLEZ MUÑOZ GC, ARCE MP, LÓPEZ B, PÉREZ C, ROMERO A, DEL BARRIO L, MARTÍN DE SAAVEDRA MD, EGEA J, LEÓN R, VILLARROYA M, LÓPEZ MG, GARCÍA AG, CONDE S, RODRÍGUEZ FRANCO MI. N acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease. Eur J Med Chem. 46: MARTÍN DE SAAVEDRA MD, DEL BARRIO L, CAÑAS N, EGEA J, LORRIO S, MONTELL E, VERGÉS J, GARCÍA AG, LÓPEZ MG. Chondroitin sulfate reduces cell death of rat hippocampal slices subjected to oxygen and glucose deprivation by inhibiting p38, NFκB and inos. Neurochem Int. 58: DEL BARRIO L, EGEA J, LEÓN R, ROMERO A, RUIZ A, MONTERO M, ALVAREZ J, LÓPEZ MG. Calcium signaling mediated through α7 and non α7 nachr stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release. Br J Pharmacol. 162: MARTINS DF, ROSA AO, GADOTTI VM, MAZZARDO MARTINS L, NASCIMENTO FP, EGEA J, LÓPEZ MG, SANTOS AR. The antinociceptive effects of AR A014418, a selective inhibitor of glycogen synthase kinase 3 beta, in mice. J Pain. 12:

4 2012 GONZÁLEZ LAFUENTE L, EGEA J, LEÓN R, MARTÍNEZ SANZ FJ, MONJAS L, PEREZ C, MERINO C, GARCÍA DE DIEGO AM, RODRÍGUEZ FRANCO MI, GARCÍA AG, VILLARROYA M, LÓPEZ MG, DE LOS RÍOS C. Benzothiazepine CGP37157 and its isosteric 2' methyl analogue provide neuroprotection and block cell calcium entry. ACS Chem Neurosci. 3: DAL CIM T, MOLZ S, EGEA J, PARADA E, ROMERO A, BUDNI J, MARTÍN DE SAAVEDRA MD, DEL BARRIO L, TASCA CI, LÓPEZ MG. Guanosine protects human neuroblastoma SH SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase 1 via PI3K/Akt/GSK 3β pathway. Neurochem Int. 61: EGEA J, MALMIERCA E, ROSA AO, DEL BARRIO L, NEGREDO P, NUÑEZ A, LÓPEZ MG. Participation of calbindin D28K in nociception: results from calbindin D28K knockout mice. Pflugers Arch. 463: EGEA J*, MARTÍN DE SAAVEDRA MD, PARADA E, ROMERO A, DEL BARRIO L, ROSA AO, GARCÍA AG, LÓPEZ MG. Galantamine elicits neuroprotection by inhibiting inos, NADPH oxidase and ROS in hippocampal slices stressed with anoxia/reoxygenation. Neuropharmacology. 62: *: corresponding author DAL CIM T, LUDKA FK, MARTINS WC, REGINATO C, PARADA E, EGEA J, LÓPEZ MG, TASCA CI. Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions. J Neurochem. 126(4): CUNHA MP, MARTÍN DE SAAVEDRA MD, ROMERO A, PARADA E, EGEA J, DEL BARRIO L, RODRIGUES AL, LÓPEZ MG. Protective effect of creatine against 6 hydroxydopamine induced cell death in human neuroblastoma SH SY5Y cells: Involvement of intracellular signaling pathways. Neuroscience 15 : JACQUES AV, RIEGER DK, MAESTRI M, LOPES MW, PERES TV, GONÇALVES FM, PEDRO DZ, TASCA CI, LÓPEZ MG, EGEA J, NASCIMENTO KS, CAVADA BS, LEAL RB. Lectin from Canavalia brasiliensis (ConBr) protects hippocampal slices against glutamate neurotoxicity in a manner dependent of PI3K/Akt pathway. Neurochem Int. 62 : ROMERO A, GOMEZ RANGEL V, EGEA J, SAMADI A, MARCO CONTELLES J, LOPEZ MG. Enantioselective neuroprotective effects of Tacripyrine ITH122 against oxygen and glucose deprivation in rat hippocampal slices. CNS Neurosci Ther. 19: PARADA E*; EGEA J*; BUENDIA I; NEGREDO P; CUNHA AC; CARDOSO S; SOARES MP; LÓPEZ MG. The microglial alpha7 acetylcholine nicotinic receptor is a key element 4

5 in promoting neuroprotection by inducing HO 1 via Nrf2. Antioxidants & Redox Signaling 19: LORRIO S, GÓMEZ RANGEL V, NEGREDO P, EGEA J, LEON R, ROMERO A, DAL CIM T, VILLARROYA M, RODRIGUEZ FRANCO MI, CONDE S, ARCE MP, RODA JM, GARCÍA AG, LÓPEZ MG. Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia. Neuropharmacology. 67: CUNHA MP, MARTÍN DE SAAVEDRA MD, ROMERO A, EGEA J, LUDKA FK, TASCA CI, FARINA M, RODRIGUES AL, LÓPEZ MG. Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson's model. ASN Neuro. 6(6) ROMERO A, EGEA J, GONZÁLEZ MUÑOZ GC, MARTÍN DE SAAVEDRA MD, DEL BARRIO L, RODRÍGUEZ FRANCO MI, CONDE S, LÓPEZ MG, VILLARROYA M, DE LOS RÍOS C. ITH12410/SC058: a new neuroprotective compound with potential in the treatment of Alzheimer's disease. ACS Chem Neurosci. 5: TENTI G, PARADA E, LEÓN R, EGEA J, MARTÍNEZ REVELLES S, BRIONES AM, SRIDHARAN V, LÓPEZ MG, RAMOS MT, MENÉNDEZ JC. New 5 unsubstituted dihydropyridines with improved CaV1.3 selectivity as potential neuroprotective agents against ischemic injury. J Med Chem. 57: ROMERO A, RAMOS E, DE LOS RÍOS C, EGEA J, DEL PINO J, REITER RJ. A review of metalcatalyzed molecular damage: protection by melatonin. J Pineal Res. 56: EGEA J, ROMERO A, PARADA E, LEÓN R, DAL CIM T, LÓPEZ MG. Neuroprotective effect of dimebon against ischemic neuronal damage. Neuroscience. 267: ROJO AI, MCBEAN G, CINDRIC M, EGEA J, LÓPEZ MG, RADA P, ZARKOVIC N, CUADRADO A. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal. 21: EGEA J, PARADA E, GÓMEZ RANGEL V, BUENDIA I, NEGREDO P, MONTELL E, RUHÍ R, VERGÉS J, RODA JM, GARCÍA AG, LÓPEZ MG. Small synthetic hyaluronan disaccharides afford neuroprotection in brain ischemia related models. Neuroscience. 265: PARADA E, BUENDIA I, LEÓN R, NEGREDO P, ROMERO A, CUADRADO A, LÓPEZ MG, EGEA J. Neuroprotective effect of melatonin against ischemia is partially mediated by alpha 7 nicotinic receptor modulation and HO 1 overexpression. J Pineal Res. 56:

6 2015 FREITAS AE, EGEA J, BUENDÍA I, NAVARRO E, RADA P, CUADRADO A, RODRIGUES AL, LÓPEZ MG. Agmatine Induces Nrf2 and Protects Against Corticosterone Effects in Hippocampal Neuronal Cell Line. Mol Neurobiol. 51: BUENDIA I, EGEA J, PARADA E, NAVARRO E, LEÓN R, RODRÍGUEZ FRANCO MI, LÓPEZ MG. The melatonin N,Ndibenzyl(N methyl)amine hybrid ITH91/IQM157 affords neuroprotection in an in vitro Alzheimer's model via hemooxygenase 1 induction. ACS Chem Neurosci. 6: EGEA J, BUENDIA I, PARADA E, NAVARRO E, RADA P, CUADRADO A, LÓPEZ MG, GARCÍA AG, LEÓN R. Melatonin sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug prodrug' mechanism of action. Br J Pharmacol. 172: BENCHEKROUN M, BARTOLINI M, EGEA J, ROMERO A, SORIANO E, PUDLO M, LUZET V, ANDRISANO V, JIMENO ML, LÓPEZ MG, WEHLE S, GHARBI T, REFOUVELET B, DE ANDRÉS L, HERRERA AROZAMENA C, MONTI B, BOLOGNESI ML, RODRÍGUEZ FRANCO MI, DECKER M, MARCO CONTELLES J, ISMAILI L. Novel tacrine grafted Ugi adducts as multipotent anti Alzheimer drugs: a synthetic renewal in tacrine ferulic acid hybrids. ChemMedChem. 10: GUERRA ÁLVAREZ M, MORENO ORTEGA AJ, NAVARRO E, FERNÁNDEZ MORALES JC, EGEA J, LÓPEZ MG, CANO ABAD MF. Positive allosteric modulation of alpha 7 nicotinic receptors promotes cell death by inducing Ca(2+) release from the endoplasmic reticulum. J Neurochem. 133: FREITAS AE, EGEA J, BUENDIA I, GÓMEZ RANGEL V, PARADA E, NAVARRO E, CASAS AI, WOJNICZ A, ORTIZ JA, CUADRADO A, RUIZ NUÑO A, RODRIGUES AL, LOPEZ MG. Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone Induced Depressive Like Behavior in Mice. Mol Neurobiol (In Press). PARADA E, BUENDIA I, NAVARRO E, AVENDAÑO C, EGEA J, LÓPEZ MG. Microglial HO 1 induction by curcumin provides antioxidant, anti neuroinflammatory and glioprotective effects. Mol Nutr Food Res. 59: BUENDIA I, PARADA E, NAVARRO E, LEÓN R, NEGREDO P, EGEA J*, LÓPEZ MG. Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD Hallmarks in Hippocampal Organotypic Cultures. Mol Neurobiol. * corresponding author (In Press). BUENDIA I, GÓMEZ RANGEL V, GONZÁLEZ LAFUENTE L, PARADA E, LEÓN R, GAMEIRO I, MICHALSKA P, LAUDON M, EGEA J, LÓPEZ MG. Neuroprotective mechanism of the novel melatonin derivative Neu P11 in brain ischemia related models. 6

7 Neuropharmacology. 99: NAVARRO E, BUENDIA I, PARADA E, LEÓN R, JANSEN DUERR P, PIRCHER H, EGEA J, LOPEZ MG. Alpha7 nicotinic receptor activation protects against oxidative stress via hemeoxygenase I induction. Biochem Pharmacol. 97: EGEA J*, BUENDIA I, PARADA E, NAVARRO E, LEÓN R, LOPEZ MG. Anti inflammatory role of microglial alpha7 nachrs and its role in neuroprotection. Biochem Pharmacol. 97: * corresponding author. MORENO ORTEGA AJ, BUENDIA I, MOUHID L, EGEA J, LUCEA S, RUIZ NUÑO A, LÓPEZ MG, CANO ABAD MF. CALHM1 and its polymorphism P86L differentially control Ca(2+) homeostasis, mitogen activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β. Aging Cell. 14: BUENDIA I, NAVARRO E, MICHALSKA P, GAMEIRO I, EGEA J, ABRIL S, LÓPEZ A, GONZÁLEZ LAFUENTE L, LÓPEZ MG, LEÓN R. New melatonin cinnamate hybrids as multi target drugs for neurodegenerative diseases: Nrf2 induction, antioxidant effect and neuroprotection. Future Med Chem. 7: BUENDIA I, MICHALSKA P, NAVARRO E, GAMEIRO I, EGEA J, LEÓN R. Nrf2 ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol Ther. 157: ZHA X, LAMBA D, ZHANG L, LOU Y, XU C, KANG D, CHEN L, XU Y, ZHANG L, DE SIMONE A, SAMEZ S, PESARESI A, STOJAN J, LOPEZ MG, EGEA J, ANDRISANO V, BARTOLINI M. Novel Tacrine Benzofuran Hybrids as Potent Multitarget Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X ray Crystallography. J Med Chem. 59: