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Article: Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimer's Disease Mouse Model: Cellular and Molecular Correlates.

Badesso, Sara / Cartas-Cejudo, Paz / Espelosin, Maria / Santamaria, Enrique / Cuadrado-Tejedor, Mar / Garcia-Osta, Ana

2022 Volume 15, Issue 1

Abstract: Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer's ... ...

Abstract	Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer's disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed; however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention.
Language	English
Publishing date	2022-12-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15010082
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Article ; Online: Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells.

Casares, Noelia / Alfaro, María / Cuadrado-Tejedor, Mar / Lasarte-Cia, Aritz / Navarro, Flor / Vivas, Isabel / Espelosin, María / Cartas-Cejudo, Paz / Fernández-Irigoyen, Joaquín / Santamaría, Enrique / García-Osta, Ana / Lasarte, Juan José

Frontiers in immunology

2023 Volume 14, Page(s) 1130044

Abstract: A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune ... ...

Abstract	A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APP
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Menthol/therapeutic use ; Amyloid beta-Protein Precursor/genetics ; T-Lymphocytes, Regulatory ; Mice, Transgenic ; Cognition ; Immunity
Chemical Substances	Menthol (1490-04-6) ; Amyloid beta-Protein Precursor
Language	English
Publishing date	2023-04-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1130044
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Article ; Online: Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer's Disease.

Cuadrado-Tejedor, Mar / Pérez-González, Marta / Alfaro-Ruiz, Rocío / Badesso, Sara / Sucunza, Diego / Espelosin, María / Ursúa, Susana / Lachen-Montes, Mercedes / Fernández-Irigoyen, Joaquín / Santamaria, Enrique / Luján, Rafael / García-Osta, Ana

International journal of molecular sciences

2021 Volume 22, Issue 21

Abstract: Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the ... ...

Abstract	Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human
MeSH term(s)	Alzheimer Disease/complications ; Amyloid beta-Peptides/adverse effects ; Amyloid beta-Protein Precursor/physiology ; Animals ; Cognition Disorders/etiology ; Cognition Disorders/metabolism ; Cognition Disorders/pathology ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/metabolism ; Mitochondria/pathology ; Phosphorylation ; Presenilin-1/physiology ; Synapses ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Presenilin-1 ; tau Proteins
Language	English
Publishing date	2021-11-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222111950
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Article ; Online: PLA2G4E, a candidate gene for resilience in Alzheimer´s disease and a new target for dementia treatment.

Pérez-González, Marta / Mendioroz, Maite / Badesso, Sara / Sucunza, Diego / Roldan, Miren / Espelosín, Maria / Ursua, Susana / Luján, Rafael / Cuadrado-Tejedor, Mar / Garcia-Osta, Ana

Progress in neurobiology

2020 Volume 191, Page(s) 101818

Abstract: Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to ... ...

Abstract	Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/therapy ; Animals ; Behavior, Animal/physiology ; Dendritic Spines ; Disease Models, Animal ; Female ; Gene Expression Regulation/genetics ; Genetic Therapy ; Group IV Phospholipases A2/physiology ; Group IV Phospholipases A2/therapeutic use ; Hippocampus ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Spatial Memory
Chemical Substances	Group IV Phospholipases A2 (EC 3.1.1.4) ; PLA2G4E protein, human (EC 3.1.1.4)
Language	English
Publishing date	2020-05-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2020.101818
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Article: Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy.

Martier, Raygene / Liefhebber, Jolanda M / García-Osta, Ana / Miniarikova, Jana / Cuadrado-Tejedor, Mar / Espelosin, Maria / Ursua, Susana / Petry, Harald / van Deventer, Sander J / Evers, Melvin M / Konstantinova, Pavlina

Molecular therapy. Nucleic acids

2019 Volume 16, Page(s) 26–37

Abstract: A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense and ... ...

Abstract	A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense and antisense transcripts cause a gain of toxicity through the accumulation of RNA foci in the nucleus and deposition of dipeptide-repeat (DPR) proteins in the cytoplasm of the affected cells. We have previously reported on the potential of engineered artificial anti-C9orf72-targeting miRNAs (miC) targeting C9orf72 to reduce the gain of toxicity caused by the repeat-containing transcripts. In the current study, we tested the silencing efficacy of adeno-associated virus (AAV)5-miC in human-derived induced pluripotent stem cell (iPSC) neurons and in an ALS mouse model. We demonstrated that AAV5-miC transduces different types of neuronal cells and can reduce the accumulation of repeat-containing C9orf72 transcripts. Additionally, we demonstrated silencing of C9orf72 in both the nucleus and cytoplasm, which has an added value for the treatment of ALS and/or FTD patients. A proof of concept in an ALS mouse model demonstrated the significant reduction in repeat-containing C9orf72 transcripts and RNA foci after treatment. Taken together, these findings support the feasibility of a gene therapy for ALS and FTD based on the reduction in toxicity caused by the repeat-containing C9orf72 transcripts.
Language	English
Publishing date	2019-02-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2019.02.001
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Article ; Online: Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors.

Rabal, Obdulia / Sánchez-Arias, Juan A / Cuadrado-Tejedor, Mar / de Miguel, Irene / Pérez-González, Marta / García-Barroso, Carolina / Ugarte, Ana / Estella-Hermoso de Mendoza, Ander / Sáez, Elena / Espelosin, Maria / Ursua, Susana / Haizhong, Tan / Wei, Wu / Musheng, Xu / Garcia-Osta, Ana / Oyarzabal, Julen

ACS chemical neuroscience

2018 Volume 10, Issue 3, Page(s) 1765–1782

Abstract: In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested ... ...

Abstract	In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC
MeSH term(s)	Acetylation/drug effects ; Alzheimer Disease/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Disease Models, Animal ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/drug effects ; Histone Deacetylases/metabolism ; Humans ; Mice ; Phosphodiesterase 5 Inhibitors/chemistry ; Phosphodiesterase 5 Inhibitors/pharmacology
Chemical Substances	Histone Deacetylase Inhibitors ; Phosphodiesterase 5 Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2018-12-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.8b00648
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Article ; Online: Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.

European journal of medicinal chemistry

2018 Volume 150, Page(s) 506–524

Abstract: We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of ... ...

Abstract	We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Cell Line ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Dose-Response Relationship, Drug ; Drug Design ; Histone Deacetylase 6/antagonists & inhibitors ; Histone Deacetylase 6/metabolism ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Molecular Structure ; Neuroglia/drug effects ; Phosphodiesterase 5 Inhibitors/chemical synthesis ; Phosphodiesterase 5 Inhibitors/chemistry ; Phosphodiesterase 5 Inhibitors/pharmacology ; Structure-Activity Relationship
Chemical Substances	Histone Deacetylase Inhibitors ; Phosphodiesterase 5 Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; HDAC6 protein, human (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98)
Language	English
Publishing date	2018-04-25
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2018.03.005
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Article ; Online: Multitarget Approach for the Treatment of Alzheimer's Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles.

Rabal, Obdulia / Sánchez-Arias, Juan A / Cuadrado-Tejedor, Mar / de Miguel, Irene / Pérez-González, Marta / García-Barroso, Carolina / Ugarte, Ana / Estella-Hermoso de Mendoza, Ander / Sáez, Elena / Espelosin, Maria / Ursua, Susana / Tan, Haizhong / Wu, Wei / Xu, Musheng / Pineda-Lucena, Antonio / Garcia-Osta, Ana / Oyarzabal, Julen

ACS chemical neuroscience

2019 Volume 10, Issue 9, Page(s) 4076–4101

Abstract: Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel ... ...

Abstract	Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors ; Acetylation ; Alzheimer Disease/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/chemistry ; Hydroxamic Acids/metabolism ; Molecular Structure ; Phosphoric Diester Hydrolases/metabolism ; Structure-Activity Relationship
Chemical Substances	Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; PDE9A protein, human (EC 3.1.4.17) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2019-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.9b00303
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Article ; Online: Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease.

Sánchez-Arias, Juan A / Rabal, Obdulia / Cuadrado-Tejedor, Mar / de Miguel, Irene / Pérez-González, Marta / Ugarte, Ana / Sáez, Elena / Espelosin, Maria / Ursua, Susana / Haizhong, Tan / Wei, Wu / Musheng, Xu / Garcia-Osta, Ana / Oyarzabal, Julen

ACS chemical neuroscience

2017 Volume 8, Issue 3, Page(s) 638–661

Abstract: A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in- ... ...

Abstract	A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Adenosine Triphosphate/metabolism ; Alzheimer Disease/drug therapy ; Alzheimer Disease/pathology ; Animals ; Cell Line, Transformed ; Cyclic GMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Leukocytes, Mononuclear ; Mice ; Microsomes, Liver/drug effects ; Models, Molecular ; Neuroglia/drug effects ; Neurons/drug effects ; Phosphodiesterase 5 Inhibitors/chemistry ; Phosphodiesterase 5 Inhibitors/pharmacology ; Phosphodiesterase 5 Inhibitors/therapeutic use
Chemical Substances	Histone Deacetylase Inhibitors ; Phosphodiesterase 5 Inhibitors ; Adenosine Triphosphate (8L70Q75FXE) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; PDE9A protein, human (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2017-03-15
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.6b00370
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Article ; Online: Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.

Journal of medicinal chemistry

2016 Volume 59, Issue 19, Page(s) 8967–9004

Abstract: Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the ... ...

Abstract	Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
MeSH term(s)	Acetylation/drug effects ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Animals ; Cell Line ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Drug Design ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacokinetics ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Mice ; Models, Molecular ; Phosphodiesterase 5 Inhibitors/chemical synthesis ; Phosphodiesterase 5 Inhibitors/chemistry ; Phosphodiesterase 5 Inhibitors/pharmacokinetics ; Phosphodiesterase 5 Inhibitors/pharmacology
Chemical Substances	Cyclic AMP Response Element-Binding Protein ; Histone Deacetylase Inhibitors ; Phosphodiesterase 5 Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2016--13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.6b00908
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