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1.
Cell Mol Life Sci ; 80(7): 178, 2023 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-37306762

RESUMEN

Inhibition of phosphodiesterase 4D (PDE4D) enzymes has been investigated as therapeutic strategy to treat memory problems in Alzheimer's disease (AD). Although PDE4D inhibitors are effective in enhancing memory processes in rodents and humans, severe side effects may hamper their clinical use. PDE4D enzymes comprise different isoforms, which, when targeted specifically, can increase treatment efficacy and safety. The function of PDE4D isoforms in AD and in molecular memory processes per se has remained unresolved. Here, we report the upregulation of specific PDE4D isoforms in transgenic AD mice and hippocampal neurons exposed to amyloid-ß. Furthermore, by means of pharmacological inhibition and CRISPR-Cas9 knockdown, we show that the long-form PDE4D3, -D5, -D7, and -D9 isoforms regulate neuronal plasticity and convey resilience against amyloid-ß in vitro. These results indicate that isoform-specific, next to non-selective, PDE4D inhibition is efficient in promoting neuroplasticity in an AD context. Therapeutic effects of non-selective PDE4D inhibitors are likely achieved through actions on long isoforms. Future research should identify which long PDE4D isoforms should be specifically targeted in vivo to both improve treatment efficacy and reduce side effects.


Asunto(s)
Enfermedad de Alzheimer , Hidrolasas Diéster Fosfóricas , Humanos , Animales , Ratones , Neuritas , Péptidos beta-Amiloides , Neuronas , Ratones Transgénicos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4
2.
Pharmacol Rev ; 73(3): 1016-1049, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34233947

RESUMEN

The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects. Interestingly, the PDE4 enzyme family consists of several subtypes and isoforms that can be modified post-translationally or can engage in specific protein-protein interactions to yield a variety of conformational states. Inhibition of specific PDE4 subtypes, isoforms, or conformational states may lead to more precise effects and hence improve the safety profile of PDE4 inhibition. In this review, we provide an overview of the variety of PDE4 isoforms and how their activity and inhibition is influenced by post-translational modifications and interactions with partner proteins. Furthermore, we describe the importance of screening potential PDE4 inhibitors in view of different PDE4 subtypes, isoforms, and conformational states rather than testing compounds directed toward a specific PDE4 catalytic domain. Lastly, potential mechanisms underlying PDE4-mediated adverse effects are outlined. In this review, we illustrate that PDE4 inhibitors retain their therapeutic potential in myriad diseases, but target identification should be more precise to establish selective inhibition of disease-affected PDE4 isoforms while avoiding isoforms involved in adverse effects. SIGNIFICANCE STATEMENT: Although the PDE4 enzyme family is a therapeutic target in an extensive range of disorders, clinical use of PDE4 inhibitors has been hindered because of the adverse side effects. This review elaborately shows that safer and more effective PDE4 targeting is possible by characterizing 1) which PDE4 subtypes and isoforms exist, 2) how PDE4 isoforms can adopt specific conformations upon post-translational modifications and protein-protein interactions, and 3) which PDE4 inhibitors can selectively bind specific PDE4 subtypes, isoforms, and/or conformations.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inhibidores de Fosfodiesterasa 4 , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Biología Molecular , Inhibidores de Fosfodiesterasa 4/farmacología , Isoformas de Proteínas , Transducción de Señal
3.
Acta Neuropathol ; 146(2): 283-299, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37286732

RESUMEN

In the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation of Id2/Id4 is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity. We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n = 9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation. Our data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation of MBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region of MBP, using epigenetic editing, we show that cellular differentiation and myelination can be bidirectionally manipulated using the CRISPR-dCas9-DNMT3a/TET1 system in vitro. Our data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination-related genes. Altering the epigenetic status of MBP can restore the differentiation capacity of OPCs and possibly boost (re)myelination.


Asunto(s)
Esclerosis Múltiple , Humanos , Esclerosis Múltiple/patología , Epigenómica , Transcriptoma , Oligodendroglía/metabolismo , Diferenciación Celular , Metilación de ADN , Vaina de Mielina/patología , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/farmacología , Proteínas Proto-Oncogénicas
4.
Brain Behav Immun ; 109: 1-22, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36584795

RESUMEN

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Inhibidores de Fosfodiesterasa 4 , Humanos , Ratones , Animales , Vaina de Mielina/metabolismo , Esclerosis Múltiple/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/uso terapéutico , Potenciales Evocados Visuales , Oligodendroglía/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Diferenciación Celular , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL
5.
Pharmacol Res ; 197: 106970, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37884069

RESUMEN

Vascular cognitive impairment (VCI) describes neurodegenerative disorders characterized by a vascular component. Pathologically, it involves decreased cerebral blood flow (CBF), white matter lesions, endothelial dysfunction, and blood-brain barrier (BBB) impairments. Molecularly, oxidative stress and inflammation are two of the major underlying mechanisms. Nitric oxide (NO) physiologically stimulates soluble guanylate cyclase (sGC) to induce cGMP production. However, under pathological conditions, NO seems to be at the basis of oxidative stress and inflammation, leading to a decrease in sGC activity and expression. The native form of sGC needs a ferrous heme group bound in order to be sensitive to NO (Fe(II)sGC). Oxidation of sGC leads to the conversion of ferrous to ferric heme (Fe(III)sGC) and even heme-loss (apo-sGC). Both Fe(III)sGC and apo-sGC are insensitive to NO, and the enzyme is therefore inactive. sGC activity can be enhanced either by targeting the NO-sensitive native sGC (Fe(II)sGC), or the inactive, oxidized sGC (Fe(III)sGC) and the heme-free apo-sGC. For this purpose, sGC stimulators acting on Fe(II)sGC and sGC activators acting on Fe(III)sGC/apo-sGC have been developed. These sGC agonists have shown their efficacy in cardiovascular diseases by restoring the physiological and protective functions of the NO-sGC-cGMP pathway, including the reduction of oxidative stress and inflammation, and improvement of vascular functioning. Yet, only very little research has been performed within the cerebrovascular system and VCI pathology when focusing on sGC modulation and its potential protective mechanisms on vascular and neural function. Therefore, within this review, the potential of sGC as a target for treating VCI is highlighted.


Asunto(s)
Disfunción Cognitiva , Enfermedades Vasculares , Humanos , Guanilil Ciclasa Soluble , Disfunción Cognitiva/tratamiento farmacológico , GMP Cíclico , Hemo , Inflamación
6.
Mol Cell Neurosci ; 120: 103719, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35283305

RESUMEN

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.


Asunto(s)
Aminopiridinas , Autorreceptores , Hipocampo , Plasticidad Neuronal , Patrones de Reconocimiento Fisiológico , Piperidinas , Pirimidinas , Receptor de Serotonina 5-HT1A , Reconocimiento en Psicología , Agonistas del Receptor de Serotonina 5-HT1 , Aminopiridinas/farmacología , Animales , Autorreceptores/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Patrones de Reconocimiento Fisiológico/efectos de los fármacos , Patrones de Reconocimiento Fisiológico/fisiología , Piperidinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico
7.
Alzheimers Dement ; 19(8): 3458-3471, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36808801

RESUMEN

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population. METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model. RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY. DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.


Asunto(s)
Disfunción Cognitiva , Demencia , Humanos , Análisis Costo-Beneficio , Disfunción Cognitiva/tratamiento farmacológico , Cognición , Años de Vida Ajustados por Calidad de Vida , Demencia/terapia
8.
Biophys J ; 121(14): 2693-2711, 2022 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-35717559

RESUMEN

Cyclic adenosine monophosphate (cAMP) is a generic signaling molecule that, through precise control of its signaling dynamics, exerts distinct cellular effects. Consequently, aberrant cAMP signaling can have detrimental effects. Phosphodiesterase 4 (PDE4) enzymes profoundly control cAMP signaling and comprise different isoform types wherein enzymatic activity is modulated by differential feedback mechanisms. Because these feedback dynamics are non-linear and occur coincidentally, their effects are difficult to examine experimentally but can be well simulated computationally. Through understanding the role of PDE4 isoform types in regulating cAMP signaling, PDE4-targeted therapeutic strategies can be better specified. Here, we established a computational model to study how feedback mechanisms on different PDE4 isoform types lead to dynamic, isoform-specific control of cAMP signaling. Ordinary differential equations describing cAMP dynamics were implemented in the VirtualCell environment. Simulations indicated that long PDE4 isoforms exert the most profound control on oscillatory cAMP signaling, as opposed to the PDE4-mediated control of single cAMP input pulses. Moreover, elevating cAMP levels or decreasing PDE4 levels revealed different effects on downstream signaling. Together these results underline that cAMP signaling is distinctly regulated by different PDE4 isoform types and that this isoform specificity should be considered in both computational and experimental follow-up studies to better define PDE4 enzymes as therapeutic targets in diseases in which cAMP signaling is aberrant.


Asunto(s)
AMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Isoformas de Proteínas/metabolismo , Transducción de Señal
9.
Cell Mol Life Sci ; 78(19-20): 6631-6644, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34482420

RESUMEN

The differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is the prerequisite for remyelination in demyelinated disorders such as multiple sclerosis (MS). Epigenetic mechanisms, such as DNA methylation, have been suggested to control the intricate network of transcription factors involved in OPC differentiation. Yet, the exact mechanism remains undisclosed. Here, we are the first to identify the DNA-binding protein inhibitors, Id2 and Id4, as targets of DNA methylation during OPC differentiation. Using state-of-the-art epigenetic editing via CRISPR/dCas9-DNMT3a, we confirm that targeted methylation of Id2/Id4 drives OPC differentiation. Moreover, we show that in the pathological context of MS, methylation and gene expression levels of both ID2 and ID4 are altered compared to control human brain samples. We conclude that DNA methylation is crucial to suppress ID2 and ID4 during OPC differentiation, a process that appears to be dysregulated during MS. Our data do not only reveal new insights into oligodendrocyte biology, but could also lead to a better understanding of CNS myelin disorders.


Asunto(s)
Diferenciación Celular/genética , Metilación de ADN/genética , Regulación de la Expresión Génica/genética , Expresión Génica/genética , Proteína 2 Inhibidora de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/genética , Factores de Transcripción/genética , Animales , Células Cultivadas , Epigénesis Genética/genética , Ratones , Vaina de Mielina/genética , Células Precursoras de Oligodendrocitos/fisiología , Remielinización/genética
10.
Eur J Neurosci ; 53(4): 1171-1188, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33340424

RESUMEN

Phosphodiesterase 4 (PDE4) inhibitors have been shown to present beneficial effects in cerebral ischemic injury because of their ability to improve cognition and target different phases and mechanisms of cerebral ischemia, including apoptosis, neurogenesis, angiogenesis, and inflammation. The present study investigated whether repeated treatment with the PDE4 inhibitor roflumilast rescued memory loss and attenuated neuroinflammation in rats following transient global cerebral ischemia (TGCI). TGCI caused memory impairments, neuronal loss (reflected by Neuronal nuclei (NeuN) immunoreactivity), and compensatory neurogenesis (reflected by doublecortin (DCX) immunoreactivity) in the hippocampus. Also, increases in the protein expression of the phosphorylated response element-binding protein (pCREB) and inflammatory markers such as the glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), were detected in the hippocampus in TGCI rats. Repeated treatment with roflumilast (0.003 and 0.01 mg/kg) prevented spatial memory deficits without promoting hippocampal protection in ischemic animals. Roflumilast increased the levels of pCREB, arginase-1, interleukin (IL) 4, and IL-10 in the hippocampus 21 days after TGCI. These data suggest a protective effect of roflumilast against functional sequelae of cerebral ischemia, which might be related to its anti-inflammatory properties.


Asunto(s)
Isquemia Encefálica , Ataque Isquémico Transitorio , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Benzamidas , Isquemia Encefálica/tratamiento farmacológico , Ciclopropanos , Proteína Doblecortina , Hipocampo , Ratas , Memoria Espacial
11.
Neurobiol Learn Mem ; 177: 107357, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33278592

RESUMEN

Augmentation of cAMP signaling through inhibition of phosphodiesterases (PDE) is known to enhance plasticity and memory. Inhibition of PDE4 enhances consolidation into memory, but less is known about the role of other cAMP specific PDEs. Here, we tested the effects of oral treatment with a selective inhibitor of PDE7 of nanomolar potency on spatial and contextual memory. In an object location task, doses of 0.3-3 mg/kg administered 3 h after training dose-dependently attenuated time-dependent forgetting in rats. Significant enhancement of memory occurred at a dose of 3 mg/kg with corresponding brain levels consistent with PDE7 inhibition. The same dose given prior to training augmented contextual fear conditioning. In mice, daily dosing before training enhanced spatial memory in two different incremental learning paradigms in the Barnes Maze. Drug treated mice made significantly less errors locating the escape in a probe-test 24 h after the end of training, and they exhibited hippocampal-dependent spatial search strategies more frequently than controls, which tended to show serial sampling of escape locations. Acquisition and short-term memory, in contrast, were unaffected. Our data provide evidence for a role of PDE7 in the consolidation of hippocampal-dependent memory. We suggest that targeting PDE7 for memory enhancement may provide an alternative to PDE4 inhibitors, which tend to have undesirable gastrointestinal side-effects.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Consolidación de la Memoria/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Prueba de Campo Abierto/efectos de los fármacos , Ratas , Ratas Long-Evans , Ratas Wistar
12.
Behav Pharmacol ; 32(6): 459-471, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34320520

RESUMEN

Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.


Asunto(s)
Aminopiridinas/farmacología , Arginasa/metabolismo , Benzamidas/farmacología , Isquemia Encefálica , Proteínas de Unión al Calcio/metabolismo , Disfunción Cognitiva , Proteínas de Microfilamentos/metabolismo , Enfermedades Neuroinflamatorias , Animales , Conducta Animal/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/inmunología , Isquemia Encefálica/psicología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Ciclopropanos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Recuperación de la Función/efectos de los fármacos , Resultado del Tratamiento , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/metabolismo
13.
J Lipid Res ; 61(6): 830-839, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32291331

RESUMEN

Niemann-Pick type C (NPC)1 disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key factor in the development of atherosclerosis and NASH. In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH, and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring a Npc1-null allele (Npc1nih ), creating a dysfunctional NPC1 protein. Npc1nih mice were fed a 2% or 6% plant stanol ester-enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1nih mice fed the plant stanol-enriched diet exhibited lower hepatic cholesterol accumulation, damage, and inflammation than regular chow-fed Npc1nih mice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular toward an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease.


Asunto(s)
Suplementos Dietéticos , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Sitoesteroles/farmacología , Animales , Colesterol/metabolismo , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Enfermedad de Niemann-Pick Tipo C/metabolismo , Sitoesteroles/uso terapéutico , Esfingolípidos/metabolismo
14.
Neurobiol Learn Mem ; 172: 107244, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32376452

RESUMEN

Fear extinction is a form of new learning that inhibits expression of the original fear memory without erasing the conditioned stimulus-unconditioned stimulus association. Much is known about the mechanisms that underlie the acquisition of extinction, but the way in which fear extinction is maintained has been scarcely explored. Evidence suggests that protein kinase A (PKA) in the frontal cortex might be related to the persistence of extinction. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP). The present study evaluated the effect of the selective PDE4 inhibitor roflumilast (ROF; 0.01, 0.03, and 0.1 mg/kg given i.p.) on acquisition and consolidation of the extinction of fear memory in male Wistar rats in a contextual fear conditioning paradigm. When administered before acquisition, 0.1 mg/kg ROF disrupted short-term (1 day) extinction recall. In contrast, 0.03 mg/kg ROF administration in the late consolidation phase (3 h after extinction learning) but not in the early phase immediately after learning improved long-term extinction recall at 11 days, suggesting potentiation of the persistence of extinction. This effect of ROF requires the first (day 1) exposure to the context. A similar effect was observed when 9 ng ROF or 30 µM 8-bromoadenosine 3',5'-cAMP (PKA activator) was directly infused in the infralimbic cortex (IL), a brain region necessary for memory extinction. The PKA activity-dependent ROF-induced effect in the IL was correlated with an increase in its brain-derived neurotrophic factor (BDNF) protein expression, while blockade of PKA with 10 µM H89 in the IL abolished the ROF-induced increase in BDNF expression and prevented the effect of ROF on extinction recall. These effects were not associated with changes in anxiety-like behavior or general exploratory behavior. Altogether, these findings suggest that cAMP-PKA activity in the IL during the late consolidation phase after extinction learning underlies the persistence of extinction.


Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Memoria/fisiología , Corteza Prefrontal/fisiología , Transducción de Señal , Aminopiridinas/administración & dosificación , Animales , Benzamidas/administración & dosificación , AMP Cíclico/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Ciclopropanos/administración & dosificación , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Ratas Wistar
15.
Synapse ; 74(6): e22150, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32056276

RESUMEN

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.


Asunto(s)
Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Privación de Sueño/complicaciones , Diclorhidrato de Vardenafil/uso terapéutico , Aminopiridinas/farmacología , Animales , Benzamidas/farmacología , Ciclopropanos/farmacología , Ciclopropanos/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Masculino , Trastornos de la Memoria/etiología , Ratones , Memoria Espacial , Diclorhidrato de Vardenafil/farmacología
16.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-33066042

RESUMEN

Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.


Asunto(s)
Esclerosis Múltiple/tratamiento farmacológico , Oligodendroglía/metabolismo , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacología , Receptores de Esfingosina-1-Fosfato/metabolismo , Animales , Humanos , Esclerosis Múltiple/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/efectos de los fármacos , Moduladores de los Receptores de fosfatos y esfingosina 1/uso terapéutico
17.
Neurobiol Learn Mem ; 159: 6-15, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30731235

RESUMEN

Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Hipocampo/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Ftalimidas/farmacología , Percepción Espacial/efectos de los fármacos , Triptófano/análogos & derivados , Animales , Conducta Animal/efectos de los fármacos , Islas de CpG/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Ratones , Virus Diminuto del Ratón , Regiones Promotoras Genéticas/efectos de los fármacos , Triptófano/farmacología
18.
Mol Cell Neurosci ; 88: 292-299, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29501719

RESUMEN

Stress during pregnancy increases the risk to develop psychological disorders such as depression during pregnancy or in the postpartum period. According to the neurotrophin hypothesis of depression, the pathophysiology of depression is caused by reduced neurotrophic activity in the brain. However, most studies only focus on the molecular changes happening to the offspring upon gestational stress. To gain insight into the potential molecular changes happening in the stressed dams, C57Bl6/J mice were stressed during their first week of gestation. At 28 days postpartum, the hippocampus and nucleus accumbens core of the dams, two brain regions heavily implicated in depression, were evaluated using immunohistochemistry to detect changes in the neurotrophin system. Gestational stress decreased the weight of the dams, increased the chance for spontaneous abortion and increased the weight of offspring. Litter size, survival rates and sex distribution were not altered as a consequence of gestational stress. Hippocampal brain-derived neurotrophic factor (BDNF) decreased following exposure to stress during pregnancy. Hippocampal protein levels of p75NTR, a low-affinity receptor for BDNF which can induce apoptosis, were increased following exposure to stress. Protein levels of p11, of which the expression is regulated by BDNF, were decreased in the hippocampus. No changes were found for TrkB immunostaining or apoptosis. Taken together, this shows that stress during pregnancy negatively affects the neurotrophin system in the hippocampus of the dams, thereby reducing hippocampal plasticity. These data confirm that gestational stress has a negative impact on pregnancy.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Péptidos de Penetración Celular/metabolismo , Hipocampo/metabolismo , Periodo Posparto/psicología , Animales , Apoptosis/fisiología , Conducta Animal , Corticosterona/metabolismo , Femenino , Ratones Endogámicos C57BL , Embarazo , Estrés Psicológico/fisiopatología
19.
Eur J Neurosci ; 45(4): 510-520, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27813297

RESUMEN

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Imidazoles/uso terapéutico , Plasticidad Neuronal , Inhibidores de Fosfodiesterasa/uso terapéutico , Triazinas/uso terapéutico , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Caspasa 9/genética , Caspasa 9/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas de Unión al ADN , Exonucleasas/antagonistas & inhibidores , Hipocampo/irrigación sanguínea , Imidazoles/farmacología , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Triazinas/farmacología
20.
Learn Mem ; 23(1): 29-37, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26670184

RESUMEN

In previous studies, we have shown that acetylcholinesterase inhibitors and phosphodiesterase inhibitors (PDE-Is) are able to improve object memory by enhancing acquisition processes. On the other hand, only PDE-Is improve consolidation processes. Here we show that the cholinesterase inhibitor donepezil also improves memory performance when administered within 2 min after the acquisition trial. Likewise, both PDE5-I and PDE4-I reversed the scopolamine deficit model when administered within 2 min after the learning trial. PDE5-I was effective up to 45 min after the acquisition trial and PDE4-I was effective when administered between 3 and 5.5 h after the acquisition trial. Taken together, our study suggests that acetylcholine, cGMP, and cAMP are all involved in acquisition processes and that cGMP and cAMP are also involved in early and late consolidation processes, respectively. Most important, these pharmacological studies suggest that acquisition processes continue for some time after the learning trial where they share a short common time frame with early consolidation processes. Additional brain concentration measurements of the drugs suggest that these acquisition processes can continue up to 4-6 min after learning.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Animales , Discriminación en Psicología/efectos de los fármacos , Donepezilo , Indanos/farmacología , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Piperidinas/farmacología , Ratas , Ratas Wistar , Reconocimiento en Psicología , Rolipram/farmacología , Escopolamina/farmacología , Diclorhidrato de Vardenafil/farmacología
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