Utilización de derivados de quinazolinas para enfermedades neurodegenerativas

Peer reviewedConsejo Superior de Investigaciones CientíficasT3 Traducción de patente europe

C/EBPβ Regulates TFAM Expression, Mitochondrial Function and Autophagy in Cellular Models of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPβ was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPβ overexpression increased TFAM promoter activity. However, downregulation of C/EBPβ in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPβ. Then, we concluded that C/EBPβ is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.This research was supported by the “MINECO” (SAF2017-85199-P to A.P.C.), UCM-Santander (PR44/21-29931 to J.A.M.-G.) and the Health Institute “Carlos III” ( PI18/00118 to E.C. and PI21/00183 to F.B.). CIBERNED is funded by the Health Institute “Carlos III”. F.B. is a Miguel Servet Fellow (CP20/0007)

Neuroprotective and anti-inflammatory effects of linoleic acid in models of parkinson’s disease: the implication of lipid droplets and lipophagy

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.This research was supported by the Health Institute “Carlos III”-CIBERNED (CB06/05/0041 and 2015/03), “MINECO” (SAF2014-52940-R, SAF2017-85199-P and SAF 2016-78666-R), “Comunidadde Madrid” (PEJ-2019-AI/SAL-12877), “Erasmus+ funding programme”, UCM-Santander (PR44/21-29931 to J.A.M.-G.), and partially supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union

Decreased CCAAT/enhancer binding protein β expression inhibits the growth of glioblastoma cells

C/EBPβ is a leucine-zipper transcription factor implicated in the control of metabolism, development, cell differentiation, and proliferation. However, it remains unclear its role in tumor development. Here, we show that down-regulation of C/EBPβ by RNA interference inhibits proliferation in the GL261 murine glioblastoma cell line, induces an arrest of the cell cycle at the G0/G1 boundary, and diminishes their transformation capacity and migration. In addition, we show that C/EBPβ regulates the expression of several DNA damage response- and invasion-related genes. Lastly, C/EBPβ depletion significantly retards tumor onset and prolongs survival in a murine orthotopic brain tumor model. Immunohistochemical analysis revealed a significant diminution of proliferating cell nuclear antigen (PCNA) labeling in tumors derived from C/EBPβ-depleted GL261 cells compared with that in controls. These results show, for the first time, the dependence of glioma cells on C/EBPβ and suggest a potential role of this transcription factor in glioma development. © 2011 IBRO.This work was supported by the Ministerio de Educacion y Ciencia grant SAF2007-62811 (to A.P.-C). CIBERNED is founded by the Instituto de Salud Carlos III. D.A.-M is a fellow of the Consejo Superior de Investigaciones Científicas.Peer Reviewe

CCAAT/enhancer binding protein beta deficiency provides cerebral protection following excitotoxic injury

11 pages, 7 figures.-- Supplementary material available online at http://jcs.biologists.org/cgi/content/full/121/8/1224/DC1The CCAAT/enhancer-binding protein beta (C/EBPbeta, also known as CEBPB) was first identified as a regulator of differentiation and inflammatory processes in adipose tissue and liver. Although C/EBPbeta was initially implicated in synaptic plasticity, its function in the brain remains largely unknown. We have previously shown that C/EBPbeta regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have demonstrated that the expression of C/EBPbeta is notably increased in the hippocampus in a murine model of excitotoxicity. Mice lacking C/EBPbeta showed a reduced inflammatory response after kainic acid injection, and exhibited a dramatic reduction in pyramidal cell loss in the CA1 and CA3 subfields of the hippocampus. These data reveal an essential function for C/EBPbeta in the pathways leading to excitotoxicity-mediated damage and suggest that inhibitors of this transcription factor should be evaluated as possible neuroprotective therapeutic agents.This work was supported by the Ministerio de Educacion y Ciencia grants SAF2004-06263-CO2-01 and SAF2007-62811 (to A.P.-C.) and SAF2004-06263-CO2-02 (to A.S.) and the Comunidad de Madrid grant GR/SAL/0033/2004 (to A.P.-C.). M.C.-C. is a post-doctoral fellow of the Consejo Superior de Investigaciones Científicas. R.L.-M is a fellow from the Ministerio de Educación y Ciencia.Peer reviewe

Uso de derivados de quinazolinas y sus composiciones farmacéuticas en enfermedades neurodegenerativas

Uso de derivados de quinazolinas y sus composiciones farmacéuticas en enfermedades neurodegenerativas. La invención se refiere a derivados heterocíclicos de quinazolinas y a su potencial para el tratamiento de enfermedades neurodegenerativas y/o neurológicas, entre otras la enfermedad de Parkinson, enfermedad de Alzheimer o esclerosis. Además, la invención se refiere a composiciones farmacéuticas que comprenden dichos compuestos derivados de quinazolinas.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patentes con informe sobre el estado de la técnic

The new iminothiadiazole derivative VP1.14 ameliorates hippocampal damage after an excitotoxic injury

Increased levels of glutamate causing excitotoxic damage accompany many neurological disorders. A well-characterized model of excitotoxic damage involves administration of kainic acid (KA), which causes limbic seizure activity and subsequent neuronal death, particularly in the CA1 and CA3 areas of the hippocampus. Inhibition of the enzyme glycogen synthase kinase-3 (GSK-3) and cAMP levels might play an important role in neuroprotection. As intracellular cAMP levels depend, in part, on the activity of the phosphodiesterase enzymes (PDEs), these enzymes have recently emerged as potential therapeutic targets for the treatment of several diseases. In previous works, we have shown a potent anti-inflammatory and neuroprotective effect of GSK-3 inhibition in a model of excitotoxicity, as well as a reduction of nigrostriatal dopaminergic neuronal cell death after phosphodiesterase 7 inhibition, which leads to an increase in cAMP levels. This study was undertaken to determine whether simultaneous inhibition of GSK-3 and PDE-7 by a novel 5-imino-1,2,4-thiadiazole compound, named VP1.14, could prevent the massive neuronal loss in the hippocampus evoked by intrahippocampal injection of KA. Here, we show that rats treated with VP1.14 showed a reduced inflammatory response after KA injection, and exhibited a significant reduction in pyramidal cell loss in the CA1 and CA3 areas of the hippocampus. Studies with hippocampal HT22 cells in vitro also showed a clear neuroprotective effect of VP1.14 and an anti-inflammatory effect shown by a decrease in the nitrite liberation and in the expression of pro-inflammatory cytokines by primary cultures of astrocytes treated with lipopolysaccharide. © 2012 International Society for Neurochemistry.This work was supported by the Ministerio de Ciencia y Tecnología (SAF2010-16365 to A.P.-C., and SAF2009-13015-C02-01 and INC-0367 to A.M.) and by Instituto de Salud Carlos III (RD07/0060/015, RETICS program) to A.M. CIBERNED is funded by the Instituto de Salud Carlos III.Peer Reviewe

POSTER 1 ¿Implication of C/EBPb in mitochondrial function and autophagy in in vitro models of Parkinson's Disease? POSTER 2 ¿DMT, compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis?

Trabajo presentado en el XIV Foro CIBERNED, celebrado en modalidad virtual del 19 al 20 de octubre de 2020

Phosphodiesterase7 inhibition activates adult neurogenesis in hippocampus and subventricular zone in vitro and in vivo

The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3′,5′-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks.This work was supported by the MINECO (Grants SAF2010-16365 and SAF2014-52940-R to A.P-C and SAF2012-33600 to C.G), by Fondo de Investigación Sanitaria; Red de Trastornos Adictivos (RD12/0028/0015 to J.A.L.M), the European Union program (Grant IPT-2012-0762-300000 to C.G.) and partially financed with FEDER funds. CIBERNED is funded by the Instituto de Salud Carlos III. J.A.M-G. is a post-doctoral fellow from CIBERNED.Peer Reviewe

Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease

Parkinson’s disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanisms of action able to protect against neuronal cell death are an urgent need. We here report the in vivo efficacy on dopaminergic neuronal protection in a PD mouse model and the lack of toxicity in zebrafish and Ames test of benzothiazole-based casein kinase-1δ (CK-1δ) nanomolar inhibitors. On the basis of these results, we propose protein kinase CK-1δ inhibitors as the possible disease-modifying drugs for PD, benzothiazole 4 being a promising drug candidate for further development as a new therapy of this neurodegenerative disease.This work was supported by grants from MINECO (SAF2012-37979-C03-01 to A.M. and SAF2014-52940-R to A.P.-C.) and from MICINN (grant SAF2010-16365 to A.P.-C.). I.G.S. and D.I.P. acknowledge a pre- and postdoctoral fellowship from MICINN (FPI program) and CSIC (JAE program), respectively. CIBERNED is funded by the Instituto de Salud Carlos III. J.A.M.-G. is a fellow from CIBERNED.Peer reviewe