Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity

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

doi:10.1016/j.nbd.2006.09.006

Cited by 57 publications

(42 citation statements)

References 46 publications

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“…These results are in accordance with previous results using rolipram as a therapeutic agent in spinal cord injury and transient global ischemia where lower doses were also more effective (Block et al, 1997, Nikulina et al, 2004. Rolipram has also been found to improve outcome in experimental allergic encephalomyelitis, Alzheimer disease, multiple sclerosis, ischemia, and striatal excitotoxicity (Genain et al, 1995, Navikas et al, 1998, Folcik et al, 1999, Gong et al, 2004, Demarch et al, 2007, Sasaki et al, 2007. Our results and the many studies assessing rolipram in models of neurological disorders suggest that use of a PDE IV antagonist may be a promising avenue of research as we search for a successful pharmacological therapy for TBI patients.…”

Section: Discussionsupporting

confidence: 89%

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Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

137

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Section: Discussionsupporting

confidence: 89%

“…Together, these results suggest that the mechanism of rolipram's action may be through CREB. This is supported in other injury models as well where rolipram significantly increased CREB phosphorylation (Nagakura et al, 2002, Hosoi et al, 2003, Lee et al, 2004, Demarch et al, 2007.…”

Section: Discussionsupporting

confidence: 66%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

137

151

View full text Add to dashboard Cite

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“…The beneficial effect of restoring CREB phosphorylation has been observed by us and others in both excitotoxic and genetic mouse models of HD [100,101]; thus pathways targeting CREB activation can also lead to an increase in BDNF together with cognitive improvements in HD models [102]. Furthermore, regulation of possible downstream effectors of BDNF function also shows clearly motor improvements together with a restoration of CREBmediated gene transcription and expression of synaptic markers in R6/1 mouse model of HD [102,103].…”

Section: Activation Of Transcription Factors: Creb and Elk-1mentioning

confidence: 56%

“…It has been shown that the expression of different PDEs is altered in the striatum [115,116] and hippocampus [38] of HD mouse models. 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].…”

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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“…Subsequent works on the same line demonstrated the early CREB-signalling dysregulation in immortalized striatal cell lines (Gines et al, 2003) and in R6/2 mice . Its reduced signalling became a promising target for therapeutic intervention; from a pharmacological point, specific phosphodiesterases inhibitors, like rolipam and TP10, were tested to maintain CREB in its active form (phosphorylated) and preserved neuronal viability (DeMarch et al, 2007;Giampa et al, 2006;Giampa et al, 2009). As a genetic approach, CREB overexpression was sufficient to rescue polyglutamine-dependent lethality in Drosophila (Iijima-Ando et al, 2005 …”

Section: Crebmentioning

confidence: 99%

Targeting Transcriptional Dysregulation in Huntington’s Disease: Description of Therapeutic Approaches

Basso¹

2012

Huntington's Disease - Core Concepts and Current Advances

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Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity

Cited by 57 publications

References 46 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

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

Targeting Transcriptional Dysregulation in Huntington’s Disease: Description of Therapeutic Approaches

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