SEARCH · Search PubMed

Results for “Rolipram”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2006

In vivo selective binding of (R)-[11C]rolipram to phosphodiesterase-4 provides the basis for studying intracellular cAMP signaling in the myocardium and other peripheral tissues.

INTRODUCTION: Phosphodiesterase-4 (PDE4) enzymes specifically break down the second messenger cAMP, thereby terminating the intracellular signaling cascade that plays an essential role in neurohormonal modulation of many physiological systems. PDE4 activity and expression are regulated by cAMP levels, suggesting that measurement of PDE4 provides an index of intracellular cAMP signaling. METHODS: Male Sprague-Dawley rats were administered (R)- or the less active enantiomer (S)-[11C]rolipram and sacrificed 30 min later with tracer retention measured in various tissues. Co-injections with saturating doses of unlabeled (R)-rolipram, (S)-rolipram and Ro 20-1724, as well as subtype-selective PDE inhibitors vinpocetine, Bay 60-7550, cilostazol and zaprinast were used to establish binding selectivity for PDE4 over PDE1, PDE2, PDE3 and PDE5 subtypes, respectively. Autoradiography was performed to substantiate results of biodistribution studies in the myocardium. RESULTS: In vivo (R)-[11C]rolipram retention was dose-dependently reduced by co-injections of (R)-rolipram and (S)-rolipram (ED50 values of 0.03 mg/kg and 0.2 mg/kg, respectively). Vinpocetine, Bay 60-7550, cilostazol and zaprinast had no effect on (R)-[11C]rolipram binding, while (R)-rolipram and Ro 20-1724 reduced the tracer uptake to nonspecific levels in PDE4-rich tissues. CONCLUSIONS: In addition to the brain, (R)-[11C]rolipram binds selectively to PDE4 across all cardiac regions, skeletal muscle, lungs and pancreas, but not in the adipose tissues. In vivo findings were confirmed by in vitro autoradiography studies, suggesting that (R)-[11C]rolipram can be applied to evaluate alterations in central and peripheral PDE4 levels and cAMP-mediated signaling.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1996

Phosphodiesterase 4 in macrophages: relationship between cAMP accumulation, suppression of cAMP hydrolysis and inhibition of [3H]R-(-)-rolipram binding by selective inhibitors.

A perplexing phenomenon identified in several tissues is the lack of correlation between inhibition of phosphodiesterase 4 (PDE4) and certain functional responses such as smooth muscle relaxation, gastric acid secretion and cAMP accumulation. Interpretation of these data is complicated further by the finding that function correlates with the ability of PDE4 inhibitors to displace [3H]rolipram [4-(3-cyclopentenyloxy-4-methoxyphenyl)-2-pyrrolidone] from a high-affinity site in rat brain that is apparently distinct from the catalytic centre of the enzyme. We have investigated this discrepancy by using guinea pig macrophages as a source of PDE4 and have confirmed that the ability of a limited range of structurally dissimilar PDE inhibitors (Org 20241, nitraquazone and the enantiomers of rolipram and benafentrine) to increase cAMP content did not correlate with their potency as inhibitors of partly purified PDE4, whereas a significant linear and rank order correlation was found when cAMP accumulation was related to the displacement of [3H]R-(-)-rolipram from a specific site identified in macrophage lysates. An explanation for these data emerged from the finding that the IC50 values and rank order of potency of these compounds for inhibition of partly purified PDE4 and the native (membrane-bound) form of the same enzyme were distinct. Similarly, no correlation was found when membrane-bound PDE4 was compared with the same enzyme that had been solubilized with Triton X-100. These unexpected results were attributable to a selective decrease in the potency of those inhibitors [nitraquazone, R-(-)- and S-(+)-rolipram] that interacted preferentially with the rolipram binding site. Indeed, if membrane-bound PDE4 was used as the enzyme preparation, excellent linear and rank order correlations between inhibition of cAMP hydrolysis, displacement of [3H]R-(-)-rolipram and cAMP accumulation were found, which improved further in the presence of the vanadyl (Vo)/2. GSH complex. Moreover, using Vo/2.GSH-treated membranes, the IC50 values of nitraquazone and the enantiomers of rolipram for the inhibition of PDE4 approached their affinity for the rolipram binding site. Collectively, these data suggest that the rolipram binding site and the catalytic domain on CPPDE4 might represent part of the same entity. In addition, these results support the concept that PDE4 can exist in different conformational states [Barnett, Manning, Cieslinski, Burman, Christensen and Torphy (1995) J. Pharmcol. Exp. Ther. 273, 674-679] and provide evidence that the cAMP content in macrophages is regulated primarily by a conformer of PDE4 for which rolipram has nanomolar affinity.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Effects of rolipram, a selective inhibitor of type 4 phosphodiesterase, on lipopolysaccharide-induced uveitis in rats.

PURPOSE: To investigate effects of rolipram, an inhibitor of type 4 phosphodiesterase, on lipopolysaccharide (LPS)-induced uveitis in Wistar rats. METHODS: A total of 100 microg LPS was injected into the rat footpad. Rolipram (Wako Pure Chemical, Osaka, Japan) was injected intraperitoneally 30 minutes before administration of LPS. Levels of intracameral protein, cells, E-selectin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nitrite were determined. E-selectin, TNF-alpha, IL-6, and inducible nitric oxide synthase (iNOS) mRNAs and immunohistochemical reactivity of nuclear factor (NF)-kappa B and TNF-alpha were also examined in the iris-ciliary body. RESULTS: After LPS injection, intracameral protein and cells increased from 18 to 30 hours later. Rolipram, however, inhibited elevation of protein and cells. After LPS injection, mRNA levels of E-selectin, TNF-alpha, and IL-6 in the iris-ciliary body increased 3 hours later, and iNOS mRNA increased 6 hours later. Elevation of mRNA levels for E-selectin, TNF-alpha, and IL-6 was inhibited by rolipram. After LPS injection, intracameral TNF-alpha and IL-6 levels increased 4 to 6 hours later, and nitrite levels increased 14 to 20 hours later. Elevation of TNF-alpha and IL-6 levels was decreased by rolipram. Rolipram did not affect iNOS mRNA and nitrite levels. Immunoreactivity of NF-kappa B was strong 1 hour after LPS injection, and was decreased by rolipram. Immunoreactivity of TNF-alpha was strong 4 hours after LPS injection and was decreased by rolipram. CONCLUSIONS: NF-kappa B translocation and expression of E-selectin, TNF-alpha, and IL-6 are involved in the pathogenesis of LPS-induced uveitis and are inhibited by rolipram. The inhibitory effect of rolipram in uveitis may be independent of iNOS synthesis.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Imaging of cAMP-specific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats.

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Effect of rolipram on relative 14C-deoxyglucose uptake in inflammatory lesions and skeletal muscle.

PURPOSE: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become a useful imaging tool for inflammatory diseases. In this study we investigated the effects of rolipram, a selective phosphodiesterase type 4 inhibitor, on 14C-deoxyglucose (DG) uptake in inflammatory lesions and other normal tissues, and attempted to improve the inflammation/muscle ratio. METHODS: To induce inflammation, mice were inoculated with turpentine oil. Inflammation-bearing mice were pretreated with rolipram (3 mg/kg i.p. or i.v.), and the effect on 14C-DG uptake was measured using a tissue dissection method and autoradiography. The inflammatory tissue samples were stained with haematoxylin and eosin. RESULTS: Rolipram (3 mg/kg i.p.) significantly decreased 14C-DG uptake in normal tissues like brain, heart and skeletal muscle (brain 31%, heart 60%, skeletal muscle 61%). On the other hand, 14C-DG uptake in inflammatory lesions was not significantly altered by pretreatment with rolipram. The inflammation/muscle ratio of 14C-DG uptake (30 min after tracer injection) was enhanced from 1.1 to 2.8 by rolipram. An autoradiographic study revealed heterogeneous distributions of 14C-DG in the inflammatory lesions and skeletal muscle of animals that were not treated with rolipram. Pretreatment with rolipram significantly attenuated the intramuscular distribution of 14C-DG, producing a relatively homogeneous distribution of radioactivity. CONCLUSION: These results indicate that rolipram decreased 14C-DG uptake in skeletal muscle by activation of the adenosine 3',5'-cyclic monophosphate system, whereas 14C-DG uptake in inflammatory lesions was not significantly altered. Therefore, rolipram may be a valuable tool for improving the visualisation of inflammatory lesions in clinical PET studies employing FDG.

Animals↗

PubMed1986

Stereospecific binding of the antidepressant rolipram to brain protein structures.

The characteristics for the binding of the selective cAMP phosphodiesterase inhibitor and antidepressant agent rolipram to brain and peripheral organs were investigated. (+/-)-[3H]Rolipram equilibrium binding and Scatchard analysis revealed saturable, reversible, stereospecific, Mg2+-dependent and heat-sensitive binding with an apparent Hill number of 1. Binding was detected both to membrane-bound and soluble sites, with dissociation constants Kd of 1.2 and 2.4 nM, respectively, and binding site concentrations (Bmax) of 19.3 and 23.6 pmol/g rat forebrain. The (-)-enantiomer of rolipram was ca. 20 times more effective than the (+)-enantiomer in displacing (+/-)-[3H]rolipram from membranes. Rolipram bound to brain tissue of all mammalian species tested including man, while tissue from bird and fish showed less binding. Organs other than brain exhibited only negligible binding. Only specific cAMP phosphodiesterase inhibitors (ICI 63.197, Ro 20-1724) were potent competitors, while rolipram itself was inactive in a variety of receptor binding assays of neuroactive ligands. The kinetics of (-)-[3H]rolipram binding to the particulate fraction revealed a complex association and dissociation behaviour. The nature of the rolipram binding protein(s) is not clear, but the low affinity binding site evident from binding kinetics may represent a rolipram-sensitive phosphodiesterase isoenzyme also common to some peripheral organs, while the high affinity binding site(s) may be related to PDE isoenzymes more confined to the central nervous system.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1994

Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor.

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.

Animals↗

PubMed1995

The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity.

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.

Adenosine↗

PubMed1993

Sequential alteration of [3H]rolipram binding in gerbil brain after transient cerebral ischemia.

The time course of rolipram (Ca2+/calmodulin independent cyclic adenosine monophosphate inhibitor) binding sites changes following gerbil transient forebrain ischemia was determined using receptor autoradiography. Gerbils subjected to 10-min ischemia revealed a significant reduction in rolipram binding in most selectively vulnerable regions early in the recirculation (1-5 h). Marked reduction in the rolipram binding was seen in the selectively vulnerable areas 48 h or 7 days after ischemia. Thereafter, the rolipram binding in the hippocampal CA1 and CA3 sectors, which were most vulnerable to ischemia, was severely reduced up to 1 month after recirculation. In contrast, the reduction of the rolipram binding activity in other regions recovered to sham-operated level or showed a slight recovery. Interestingly, the dentate gyrus, which was resistant to ischemia, also exhibited a significant reduction of the rolipram binding activity up to 1 month after ischemia. Eight months after ischemia, the hippocampal CA1 and CA3 sectors showed severe shrinkage and marked reduction in the rolipram binding. Other regions exhibited no significant reduction in the rolipram binding except for a slight reduction in the thalamus. These results demonstrate that transient cerebral ischemia causes severe reduction in rolipram binding sites in selectively vulnerable areas, and this reduction precedes the neuronal cell loss. These findings may reflect the alteration of an intracellular phosphodiesterase activity after ischemia.

Animals↗

PubMed2001

Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward.

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Preliminary evidence for an involvement of the cholinergic system in the sedative effects of rolipram in rats.

Rolipram is a specific cAMP phosphodiesterase type 4 (PDE4) inhibitor in the brain, which induces an increase in the intracellular levels of cAMP. Rolipram produces characteristic alterations in animal behavior, which have been suggested to be mediated mainly through an intracellular mechanism involving an increase in cAMP. However, specific mechanisms mediating the sedative effects of this compound have not yet been investigated. Because several lines of evidence indicate that the acetylcholine neural system may be involved in some effects of PDE4 inhibitors, the aim of this study was to elucidate whether the neurotransmitter acetylcholine is involved in the sedative effects induced by rolipram. The present study assessed the motor effects of rolipram in an exploratory behavioral test, the open field, in Wistar rats. The results show that rolipram (0.1-3.0 mg/kg SC) induced potent and dose-dependent hypoactivity, decreasing both locomotion and rearing. Physostigmine (0.03-0.3 mg/kg SC) potentiated a subeffective dose of rolipram (0.03 mg/kg SC), resulting in strong sedation, similar to that following higher doses of either rolipram or physostigmine alone, whereas the reduction in locomotor activity induced by rolipram (0.3 mg/kg SC) was completely reversed by scopolamine (0.03-0.3 mg/kg SC). These data provide preliminary evidence suggesting the involvement of the acetylcholinergic system in the sedative effects of rolipram.

Acetylcholine↗

PubMed1990

Effects of lithium and rolipram enantiomers on locomotor activity in inbred mice.

Rolipram is a racemic drug that increases brain cAMP availability by inhibiting phosphodiesterase. Lithium, on the other hand, reduces cAMP levels in brain by inhibiting adenylate cyclase and by increasing phosphodiesterase activity. Inbred strains of mice were used in the present study to determine whether the opposite effects of lithium and rolipram on cAMP levels were evident from behavioural effects of the drugs. In the first experiment, locomotor activity was measured in strains of male and female mice given an injection of either vehicle, (+)- or (-)-rolipram in order to find appropriate test conditions for studying interactions with lithium. (-)-Rolipram was more potent than its antipode in inducing hypokinesia, and the effects of (+)- and (-)-rolipram depended on mouse strain. In the second experiment, mice received lithium in their food for 3-4 weeks prior to testing, and they were then given an injection of vehicle, (+)- or (-)-rolipram before behaviour tests. Lithium reduced locomotor activity in mice given the vehicle, whereas it counteracted activity-suppressant effects of rolipram. The behavioural findings are consistent with the opposite pharmacological effects of lithium and rolipram on cAMP, and support the notion that cAMP availability in brain may play a role in behavioural effects of lithium and rolipram.

Animals↗

PubMed1994

The inotropic mechanism of the phosphodiesterase inhibitor OPC 3911 alone and in combination with rolipram, studied in papillary muscles of ferret and guinea-pig and isolated myocytes of guinea-pig ventricular muscle.

OPC 3911 is a potent inhibitor and PDE III is a specific inhibitor in cardiac muscle. The effects of the drug alone and in combination with the non-inotropic PDE IV inhibitor rolipram were analysed using hearts from guinea-pigs and ferrets. OPC 3911 had an EC50 value of 0.1 microM. At 0.1 microM peak force was increased by 50.7 +/- 7.6% (n = 6, P < 0.001), time to peak tension (TPT) reduced by 18.7 +/- 5.6% (n = 6, P < 0.05). Time to half relaxation (THR) was prolonged by 19 +/- 4.2% (n = 6, P < 0.001). After addition of rolipram (30 microM), there was a potentiation of peak force at all concentrations of OPC 3911. At 0.1 microM OPC rolipram increased peak force by 82.8 +/- 8.9% (n = 6, P < 0.001), reduced TPT by 73 +/- 6% (n = 6, P < 0.005) and increased THR by 27 +/- 5% (P < 0.01). OPC 3911 shortened action potential duration (APD) at 50% repolarization by 5.3 +/- 2.5% (n = 6, P < 0.05). Addition of rolipram prolonged APD by 3.7 +/- 2.5% (n = 6, P < 0.05). Second inward current (Isi) was increased at 3 microM OPC 3911 by 46 +/- 6% (n = 6, P < 0.05). The combination of OPC 3911 and rolipram intensified the Isi to 101 +/- 5% (n = 3). Rolipram slowed the rate of restitution and the onset of restitution was prolonged. Relative maximum post-extrasystolic potentiation was reduced in the presence of OPC 3911 from 67 +/- 5% to 45 +/- 6%. Adding rolipram caused potentiation of 55 +/- 6%. OPC 3911 increased the recirculation fraction of activator calcium from 0.36 to 0.42 (n = 10, P < 0.05). After addition of rolipram the recirculation fraction was 0.41 +/- 0.04 (n = 10, P < 0.05). The results suggest that rolipram exerts its potentiating effect on OPC 3911 via an increased Isi.

Action Potentials↗

PubMed1994

Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor.

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1994

Effects of rolipram on responses to acute and chronic antigen exposure in monkeys.

The following study was performed to test the hypothesis that treatment with rolipram, a specific inhibitor of phosphodiesterase (PDE) IV, should inhibit many pulmonary responses to acute and chronic antigen challenge in atopic monkeys by elevating intracellular cAMP and subsequently inhibiting leukocyte function. Monkeys received subcutaneous injections of either vehicle (2% DMSO) or 10 mg/kg of rolipram 1 h before exposure to Ascaris suum antigen (Ag). Acute responses to Ag, including bronchoconstriction, pulmonary leukocyte infiltration, and cytokine production, were monitored before and 4 h after single Ag aerosol administration. To monitor the effects of rolipram on chronic Ag exposure, a 10-d, multiple-Ag protocol, previously demonstrated to induce airway hyperresponsiveness (AHR) to methacholine (MCh), was performed. Ag exposure increased respiratory system resistance (Rrs) 221.7 +/- 31.88% (n = 5). This increase in Rrs was not significantly altered by rolipram. Rolipram significantly (p < 0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5). Ag-induced increases in BAL IL-8 and TNF were significantly reduced by rolipram, but IL-1 beta and IL-6 increases were unaffected (n = 9). Ag-induced increases in BAL eosinophils and neutrophils were significantly reduced by rolipram (n = 9). In the multiple-Ag protocol (n = 7), rolipram significantly reduced both the number of BAL eosinophils (p < 0.02) and the development of AHR (p < 0.002). Despite its inability to inhibit acute Ag-induced bronchoconstriction, rolipram was protective against acute and chronic inflammatory responses to Ag and prevented the development of AHR, suggesting that selective PDE-IV inhibition is a relevant target for asthma therapy.

Animals↗

PubMed1998

Effect of rolipram on age-related changes in cyclic AMP-selective phosphodiesterase in the rat brain: an autoradiographic study.

Rolipram is a clinically effective antidepressant with cyclic AMP-selective phosphodiesterase (cyclic-AMP PDE) inhibiting action. In this study, we investigated the effect of chronic treatment with rolipram on age-related changes in cyclic-AMP PDE in the rat brain visualized and quantitated by in vitro [3H]rolipram autoradiography. Rolipram (0.01 mg/kg and 0.1 mg/kg) or its vehicle was administered orally to 15-week-old (young) and 80-week-old (aged) Wistar rats once a day for 4 weeks. In control young rats, high [3H]rolipram binding was seen in the hippocampus, the cerebellum and the neocortex. In control aged rats, the [3H]rolipram binding decreased strikingly in almost all brain regions. Chronic treatment of the young rats with rolipram reduced the [3H]rolipram binding in a dose-dependent manner. By contrast, the same treatment of the aged rats induced no or minimal changes. These results suggest that 1) cyclic-AMP PDE in the rat brain is subject to age-associated decline, and 2) the response to rolipram treatment is different between young and aged rats.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity.

PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL-10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated. METHODS: Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested. RESULTS: Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture. CONCLUSIONS: Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect.

Adoptive Transfer↗

PubMed1985

Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain.

The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.

Animals↗