Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease

DeMarch, Zena; Giampà, Carmela; Patassini, Stefano; Bernardi, Giorgio; Fusco, Francesca R.

doi:10.1016/j.nbd.2008.02.010

Cited by 112 publications

(91 citation statements)

References 58 publications

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“…Lastly, the elevation of cAMP in the brain is thought to have beneficial effects in models of tissue injury or neurodegeneration. Rolipram enhances axonal growth and neuronal survival in a rodent spinal cord injury model (Nikulina et al, 2004) and delays the onset and progression of atrophy and disease phenotypes in the R6/2 mouse model of Huntington's disease (DeMarch et al, 2008). Despite the validation of PDE4 as a therapeutic drug target, success in the clinical development of inhibitors has been hindered by a number of dose-limiting side effects, most notably nausea, emesis, and gastric acid secretion, which have been observed with both the first-generation inhibitors such as rolipram but also with second-generation inhibitors such as cilomilast.…”

Section: Introductionmentioning

confidence: 99%

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Rutter

Poffe

Cavallini

et al. 2014

J Pharmacol Exp Ther

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Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe doselimiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-b] pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC 50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC 50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was .150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was .10 versus ,1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

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Section: Introductionmentioning

confidence: 99%

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Rutter

Poffe

Cavallini

et al. 2014

J Pharmacol Exp Ther

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“…Evidence indicates that persistence of memory for a fear-motivated task can be selectively produced by administration, at a late interval (12 h) after training, of brain-derived neurotrophic factor (BDNF) into the hippocampus and disrupted by hippocampal protein synthesis inhibition at the same time point (Bekinschtein et al 2007(Bekinschtein et al , 2008. Since treatment with rolipram can increase BDNF levels in the rat brain (Nibuya et al 1996;DeMarch et al 2008), and the late phase of rolipram-induced LTP is dependent on BDNF (Navakkode and Korte 2012), an increase in amygdalar BDNF levels emerges as a candidate mechanism involved in mediating memory persistence induced by intra-BLA rolipram. Importantly, increases in amygdalar BDNF levels might be involved in mediating long-term memory persistence (Ou et al 2010 that intra-BLA rolipram leads to enhanced BDNF levels in other areas, which might be involved in mediating the enhanced NOR memory observed in the present study.…”

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confidence: 99%

Administration of the phosphodiesterase type 4 inhibitor rolipram into the amygdala at a specific time interval after learning increases recognition memory persistence

et al. 2012

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Here we show that administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram into the basolateral complex of the amygdala (BLA) at a specific time interval after training enhances memory consolidation and induces memory persistence for novel object recognition (NOR) in rats. Intra-BLA infusion of rolipram immediately, 1.5 h, or 6 h after training had no effect on retention tested at 1, 7, and 14 d later. However, rolipram infused 3 h post-training promoted memory persistence for up to at least 14 d. The findings suggest that PDE4 inhibition in the BLA can enhance long-term memory formation when induced specifically 3 h after learning.

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“…The use of drugs that maintains CREB phosphorylated, like the specific PDE4 and 10 inhibitors rolipram and T10, decreases striatal cell loss after the injection of QUIN in an excitotoxic model of HD [100,117]. Following this research, the same group reported that administration of rolipram in R6/2 mice enhanced the expression of both phosphorylated CREB and BDNF in striatal neurons and ameliorated neurodegeneration, decreased mhtt inclusions preventing the sequestration of CBP, reduced microglia activation and rescue motor function [118,119]. Likewise, beneficial effects of PDE inhibition on cognitive function were also observed in the hippocampus of HD mouse model [101].…”

Section: Role Of Phosphodiesterasesmentioning

confidence: 93%

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

Anglada-Huguet¹,

Vidal-Sancho²,

Cabezas-Llobet³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the exon-1 of the huntingtin (htt) gene. The presence of mutant htt (mhtt) results in multiple physiopathological changes, including protein aggregation, transcriptional deregulation, decreased trophic support, alteration in signaling pathways and excitotoxicity. Indeed, the presence of mhtt induces changes in the activities/levels of different kinases, phosphatases and transcription factors that can impact on cell survival. Many studies have provided evidence that transcription may be a major target of mhtt, as gene dysregulation occurs before the onset of symptoms. The greatest number of downregulated genes in HD has led to test the ability of a large number of compounds to restore gene transcription in mouse models of HD. On the other hand, mhtt engenders multiple cellular dysfunctions including an increase of pathological glutamate-mediated excitotoxicity. For that reason, targeting the excess of glutamate has been the goal for many promising drugs leading to clinical trials. Although advances in developing effective therapies are evident, currently, there is no known cure for HD and existing symptomatic treatments are limited.

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Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease

Cited by 112 publications

References 58 publications

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Administration of the phosphodiesterase type 4 inhibitor rolipram into the amygdala at a specific time interval after learning increases recognition memory persistence

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

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