Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents

Zhang, Bo; Yang, Lihua; Konishi, Y.; Maeda, Nobuji; Sakanaka, Masahiro; Tanaka, Junya

doi:10.1016/s0028-3908(01)00174-5

Cited by 81 publications

(47 citation statements)

References 36 publications

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“…The insert in Figure 1C shows the morphology of a dibutyryl-cAMP-treated process-bearing macrophage with numerous slender, up to 10 m long filopodia (arrows) and a lamellopodial structure. Effects on microglial proliferation were not the primary focus of the current study; however, a 48-h treatment with 1 mM dibutyrylcAMP did lead to a noticeable reduction in microglial cell number, in line with other studies on microglial proliferation (Zhang et al, 2002). Gradual loss of the ramified morphology of microglia was also seen with increasing amount of forskolin, a direct inducer of adenylate cyclase, the cAMP-synthesizing enzyme , with first effects, particularly a broadening of the perinuclear cytoplasm at 10 M (Fig.…”

Section: Co) B-dsupporting

confidence: 88%

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems

Kalla

Bohatschek

Kloss

et al. 2002

Glia

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Reduction in microglial branching is a common feature in brain pathology and culminates in the transformation into small, rounded, microglia-derived phagocytes in the presence of neural debris. The molecular factors responsible for this transformation are unknown. Here we explored the effect of different classes of intra-and extracellular stimuli in vitro on the morphology of ramified microglia cultured on a confluent astrocyte substrate. These studies showed a strong dose-dependent effect for the Ca 2ϩ ionophore calcimycine/A21837 (50 M) and for dibutyryl-cAMP (1 mM), with a loss of microglial ramification. Direct activation of the adenylate cyclase with forskolin (0.1 mM) also led to the disappearance of microglial branching. Okadaic acid (70 nM), the inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), and pertussis toxin (12.5 g/ml), a G i -protein inhibitor, also showed similar effects. No effect was observed for dibutyryl-cGMP or for UTP; addition of ATP had a moderate effect, but only at very high, probably nonphysiological concentrations (100 mM). Extracellular matrix components such as keratatan-sulfate, integrin receptor blockers, the disintegrins kistrin, echistatin, and flavoridin, or the serine protease thrombin all had no effect. Addition of prostaglandin D 2 (PGD 2 ), a molecule produced by activated microglial cells, had a transforming effect, but at concentrations two orders of magnitude higher than that of established PGD 2 receptors. In summary, addition of agents causing intracellular elevation of Ca 2ϩ and cAMP or inhibition of G i -proteins and phosphatases to ramified microglia cultured on top of confluent astrocytes leads to a rapid loss of microglial branching. Signaling cascades controlled by these molecules may play an important role in the regulation of this common physiological process in the injured brain.

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Section: Co) B-dsupporting

confidence: 88%

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems

Kalla

Bohatschek

Kloss

et al. 2002

Glia

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“…This second messenger has been reported to inhibit certain proinflammatory pathways such as the LPS-induced p38 and JNK pathways (32)(33)(34). However, in this study we show that AM/AMBP-1 also induces PPAR-␥ expression in LPS stimulated macrophages in vitro and in vivo.…”

Section: Discussioncontrasting

confidence: 66%

“…In our present study, the cAMP analog DBcAMP and PDE inhibitors were able to decrease LPS-induced TNF-␣ release from RAW 264.7 macrophages. DBcAMP is an analog of the naturally occurring cAMP and has been shown to activate the downstream signaling pathways of the natural second messenger cAMP (33,47). There is a variety of PDEs that rapidly terminate the effect of the second messenger cAMP.…”

Section: Discussionmentioning

confidence: 99%

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Miksa

Cui

et al. 2007

The Journal of Immunology

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Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-γ expression in vivo and in vitro and was associated with increased TNF-α production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-γ levels in both models, resulting in TNF-α suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-α production in the absence of PPAR-γ. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced ΤΝF-α release, it did not alter PPAR-γ expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-γ and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-γ.

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“…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). There are also very modest increases in cGMP levels with high concentrations of rolipram, suggesting that rolipram could work through cGMP although this is more unlikely (Van Staveren et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

132

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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Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents

Cited by 81 publications

References 36 publications

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Modulation of the cAMP signaling pathway after traumatic brain injury

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Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents

Cited by 81 publications

References 36 publications

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and Gi‐protein systems

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and Gi‐protein systems

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Modulation of the cAMP signaling pathway after traumatic brain injury

Contact Info

Product

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Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and G_i‐protein systems