Selective inhibition of one of the cyclic AMP phosphodiesterases from rat brain by the neurotropic compound rolipram

Némoz, Georges; Prigent, Annie‐France; Moueqqit, Mohammed; Fougier, Sylvie; Macovschi, O; Pachéco, H.

doi:10.1016/0006-2952(85)90029-2

Cited by 57 publications

(21 citation statements)

References 15 publications

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“…PDE IV selectively degrades cAMP (K m 4 μM) as compared to cGMP (K m >3000 μM), and is inhibited by the highly specific inhibitor, rolipram (Nemoz et al, 1985, Muller et al, 1996, Torphy, 1998. In the uninjured CNS, rolipram increases cAMP levels in the hippocampus (Barad et al, 1998, Van Staveren et al, 2001, Giorgi et al, 2004, and specifically in microglia and astrocytes as compared to neurons (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

137

151

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“…This (10,22,23) and a Km for cAMP of =2 ,uM. This type of enzyme binds to, and is inhibited (10,(23)(24)(25)(26)(27) …”

Section: Discussionmentioning

confidence: 99%

Cloning and characterization of mammalian homologs of the Drosophila dunce+ gene.

Davis

Takayasu²,

Eberwine³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

135

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A probe representing the Drosophila dunce'(dnc') gene, the structural gene for a cAMP phosphodiesterase (PDEase), detects homologous sequences in many different organisms, including mouse, rat, and human. Genomic and cDNA clones representing a homolog of the Drosophila dnc' gene were isolated from rat libraries and characterized. This gene has been named ratdnc-1. One cDNA clone defines a large open reading frame of 41.8 kilobases (kb), predicting a protein sequence of 610 amino acids with significant homology to a conserved domain of -275 residues found in most otherPDEases. The amino acid identity value to the Drosophila cAMP PDEase within this domain is a striking 75%. Other cDNA clones show blocks of sequence divergence from this cDNA clone close to the predicted N terminus, indicating the potential existence of a family of related enzymes encoded by alternatively spliced messenger RNAs from ratdnc-1. Genomic blotting experiments suggest the existence of at least one other rat gene with homology to ratdnc-1. RNAs homologous to ratdnc-1 are heterogeneous in size between tissues, with heart containing a major transcript of 4.4 kb and brain one of4.0 kb.The potential identity of the product of the ratdnc-1 gene with known PDEases is discussed.

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“…Specifically, we examined the effects of rolipram, a PDE IV inhibitor (19), siguazodan, an inhibitor of the cyclic GMP-inhibited PDE (PDE III) (20), and zaprinast, an inhibitor of the cyclic GMPspecific PDE (PDE V) (21) on the following eosinophil functions: a) superoxide generation, b) endothelial cell adhesion, and c) infiltration into the airways.…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase IV Inhibitors as Therapy for Eosinophil-Induced Lung Injury in Asthma

Torphy¹,

Barnette²,

Hay³

et al. 1994

Environmental Health Perspectives

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Asthma is a complex, multifactorial disease that is underpinned by airway inflammation. A variety of cytotoxic substances are released into the airway from infiltrating inflammatory cells, especially the eosinophil. These cytotoxic substances, including reactive oxygen metabolites, produce damage to the airway epithelium, a histologic feature of chronic asthma. Damage to the airway epithelium, in turn, is thought to be a major factor responsible for the development of airway hyperreactivity, a hallmark of asthma. One notable molecular target for novel antiasthmatic drugs is the cyclic AMP-specific phosphodiesterase (PDE) or PDE IV. This isozyme is the predominant form of cyclic nucleotide PDE activity in inflammatory cells. Thus, in view of the putative role of cyclic AMP as an inhibitory second messenger in these cells, PDE IV inhibitors have been shown to suppress inflammatory cell activity. The purpose of the present experiments was to examine the effect of the PDE IV inhibitor, R-rolipram, on three key functions of the guinea pig eosinophil: a) superoxide anion (°O) production, b) adhesion to human umbilical vein endothelial cells (HUVECs), and c) infiltration into the airway. R-rolipram-elevated eosinophil cyclic AMP content (EC50= 1.7 pM) and inhibited fMLP-induced°2 production in a concentration-dependent manner (IC50=0.3 pM). In contrast, neither siguazodan, a PDE IlIl inhibitor, nor zaprinast, a PDE V inhibitor, had an appreciable effect. R-rolipram (30 pM) also reduced by 25 to 40% the adhesion of eosinophils to HUVECs stimulated with phorbol myristate acetate or tumor necrosis factor-a, particularly under conditions in which both cell types were simultaneously exposed to the PDE IV inhibitor. Again, siguazodan and zaprinast had little or no effect. Finally, pretreatment of conscious guinea pigs with R-rolipram (1-10 mg/kg, intragastric) produced a dose-dependent inhibition of antigen-induced eosinophil infiltration into the airway. Thus, by virtue of their ability to modify eosinophil function at several levels, PDE IV inhibitors may reduce epithelial cell damage associated with asthma. - 270-5381. that the loss of the airway epithelium leads to airway hyperreactivity by exposing subepithelial sensory nerve endings to the external environment (6,7). Consequently, noxious environmental stimuli more easily activate these nerve endings to cause antidromic release of bronchoconstricting neuropeptides (e.g., substance P) from Cfibers via an axon reflex (6,7).The inflammatory cell primarily responsible for damaging the airway epithelium is the eosinophil (Figure 1). Eosinophils are recruited into asthmatic airways and activated by a variety of lipid mediators (e.g., leukotriene B4, platelet activating factor) and cytokines (e.g., tumor necrosis factor-a, interleukin-5) (3,8). Activated eosinophils release both proinflammatory and cytotoxic substances (3,8,9). In particular, these cells release cationic proteins (e.g., major basic protein, eosinophil cationic protein) and reactive oxygen metabolites (e.g...

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Selective inhibition of one of the cyclic AMP phosphodiesterases from rat brain by the neurotropic compound rolipram

Cited by 57 publications

References 15 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Cloning and characterization of mammalian homologs of the Drosophila dunce+ gene.

Phosphodiesterase IV Inhibitors as Therapy for Eosinophil-Induced Lung Injury in Asthma

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