更新于：2024-11-01

PDE7 x GSK-3

更新于：2024-11-01

基本信息

关联

项与 PDE7 x GSK-3 相关的药物

VP3.15 (Consejo Superior de Investigaciones Científicas)

靶点

GSK-3 x PDE7

作用机制

GSK-3抑制剂 [+1]

在研机构

Consejo Superior de Investigaciones Científicas

原研机构

Consejo Superior de Investigaciones Científicas

在研适应症

视网膜色素变性

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PDE7 x GSK-3 相关的临床结果

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100 项与 PDE7 x GSK-3 相关的转化医学

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0 项与 PDE7 x GSK-3 相关的专利（医药）

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项与 PDE7 x GSK-3 相关的文献（医药）

2014-03-19·ACS Chemical Neuroscience3区 · 医学

Crosstalk between Phosphodiesterase 7 and Glycogen Synthase Kinase-3: Two Relevant Therapeutic Targets for Neurological Disorders

3区 · 医学

Article

作者: Morales-Garcia, Jose A. ; Martinez, Ana ; Alonso-Gil, Sandra ; Gil, Carmen ; Redondo, Miriam ; Palomo, Valle ; Perez-Castillo, Ana

Chronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Previous data from our group have shown that different inhibitors of the cyclic adenosine monophosphate (cAMP) specific phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) enzymes are potent anti-inflammatory agents in different models of brain injury. In this study, we investigated cross-talk between PDE7 and GSK-3, two relevant therapeutic targets for neurological disorders, using a chemical approach. To this end, we compared specific inhibitors of GSK-3 and PDE7 with dual inhibitors of both enzymes with regard to anti-inflammatory effects in primary cultures of glial cells treated with lipopolysaccharide. Our results show that the GSK-3 inhibitors act exclusively by inhibition of this enzyme. By contrast, PDE7 inhibitors exert their effects via inhibition of PDE7 to increase intracellular cAMP levels but also through indirect inhibition of GSK-3. Activation of protein kinase A by cAMP results in phosphorylation of Ser9 of GSK-3 and subsequent inhibition. Our results indicate that the indirect inhibition of GSK-3 by PDE7 inhibitors is an important mechanism that should be considered in the future development of pharmacological treatments.

2013-09-01·Neurobiology of Aging2区 · 医学

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

2区 · 医学

Article

作者: Desiree Antequera ; Consuelo Pascual ; Carmen Gil ; Virginia Pérez-Grijalba ; Rocio Perez-Gonzalez ; Isidro Ferrer ; Daniel I. Perez ; Miriam Redondo ; Ana Martinez ; Eva Carro ; Agnieszka Krzyzanowska ; Marta Bolos ; Manuel Sarasa

Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aβ deposition; (3) enhanced astrocyte-mediated Aβ degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.

2013-01-01·Neuropharmacology2区 · 医学

Dual inhibitor of PDE7 and GSK-3 – VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice

2区 · 医学

Article

作者: Tatiana V. Lipina ; Valle Palomo ; Carmen Gil ; John C. Roder ; Ana Martinez

Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed. Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades. We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins. In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities. VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis. VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit. The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects. The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning. Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries. This article is part of a Special Issue entitled 'Cognitive Enhancers'.