Effects of phosphodiesterase inhibitors on cytokine production by microglia

Yoshikawa, M; Suzumura, A.; Tamaru, Tsukasa; Takayanagi, Tetsuya; Sawada, Makoto

doi:10.1191/135245899678847194

Cited by 10 publications

(10 citation statements)

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“…These results gave a reasonable explanation for previous findings that H89 completely reversed the effect of dibutyryl-cAMP (dbcAMP) or forskolin on LPS-induced IL-10 elevation (Woo et al 2003(Woo et al , 2004, but only partially blocked the dbcAMP, PGE 2 , or forskolin-mediated inhibition of TNF-α (Petrova et al 1999;Woo et al 2003Woo et al , 2004. Although previous studies reported conflicting results about the effect of cAMP on IL-1β expression (Petrova et al 1999;Woo et al 2003Woo et al , 2004Yoshikawa et al 1999), those Figure 4 Schematic representation of the respective roles of PKA vs Epac pathways on MAPK p38 pathway and GSK-3β pathway in the LPS-stimulated microglia. LPS binds to toll like receptor 4 (TLR4) and activates downstream adaptor proteins, thereby p38 is phosphorylated at Thr180/Tyr182 by MKK3/6, and the level of phosphorylated GSK-3β (at Ser9) reduces possibly due to the activation of protein phosphatase (PP).…”

Section: Discussionsupporting

confidence: 72%

Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia

et al. 2010

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To further understand the anti-inflammatory effect of adenosine cyclic 3',5'-monophosphate (cAMP), we examined the effect of protein kinase A (PKA) and cAMP-responsive guanine nucleotide exchange factor (Epac) on the transcription and production of cytokines and on the activity of mitogen-activated protein kinases (MAPK) p38 and glycogen synthase kinase-3β (GSK-3β) in endotoxin-treated rat primary cultured microglia. The PKA specific agonist N6-benzoyladenosine-3,5-cAMP (6-Bnz-cAMP) not only inhibited the transcription and production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) but also enhanced the transcription and expression of IL-10, while the Epac selective analog 8-(4-chlorophenylthio)-2-O-methyladenosine-3,5-cAMP (8-pCPT-2'-O-Me-cAMP) merely repressed the TNF-α expression. Western blots assays indicated that 6-Bnz-cAMP significantly inhibited lipopolysaccharide-induced activation of both p38 and GSK-3β in a dose-dependent manner; in contrast, 8-pCPT-2'-O-Me-cAMP only slightly repressed GSK-3β activity at large doses. Pretreatment with H-89, a specific PKA antagonist, could completely reverse the effect of 6-Bnz-cAMP on cytokines expressions and kinases activities but had no effect on the performance of 8-pCPT-2'-O-Me-cAMP. Our findings indicate that PKA and Epac exert differential effect on the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-10, possibly owing to the different effects on the downstream effectors, MAPK p38, and GSK-3β.

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Section: Discussionsupporting

confidence: 72%

Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia

et al. 2010

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“…(34) reported that PPF, a type III-IV specific PDEI, although decreasing in a dosedependent manner the production of the inflammatory cytokines TNF-α, IL-1 and IL-6 by LPS-activated microglial cells in vitro, increased up to three times the production of IL-10, an inhibitory cytokine, which is recognized to impair cytokine production of Th1 lymphocytes. Besides IL-10 also inhibits the activation of macrophages and microglia induced by IFN-δ (34).…”

Section: Discussionmentioning

confidence: 99%

“…In the CNS, PPF acts as a glial modulator, with direct actions on microglia, decreasing microglial proliferation and expression of inflammatory cytokines in vitro, such as tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) (33,34). Regulation of cytokine production by leukocytes includes the adenylate cyclase -cAMP -protein kinase pathway, which also affects the activity of a great number of other cell types (35).…”

Section: Discussionmentioning

confidence: 99%

Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats

Bondan

Martins

Bernardi

2015

Arch. Endocrinol. Metab.

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Objective: The diabetic state induced by streptozotocin injection is known to impair oligodendroglial remyelination in the rat brainstem following intracisternal injection with the gliotoxic agent ethidium bromide (EB). In such experimental model, propentofylline (PPF) recently showed to improve myelin repair, probably due to its neuroprotective, antiinflammatory and antioxidant effects. The aim of this study was to evaluate the effect of PPF administration in diabetic rats submitted to the EB-demyelinating model. Materials and methods: Adult male rats, diabetic or not, received a single injection of 10 microlitres of 0.1% EB solution into the cisterna pontis. For induction of diabetes mellitus the streptozotocin-diabetogenic model was used (50 mg/kg, intraperitoneal route -IP). Some diabetic rats were treated with PPF (12.5 mg/kg/day, IP route) during the experimental period. The animals were anesthetized and perfused from 7 to 31 days after EB injection and brainstem sections were collected for analysis of the lesions by light and transmission electron microscopy. Results: Diabetic rats injected with EB showed larger amounts of myelin-derived membranes in the central areas of the lesions and considerable delay in the remyelinating process played by surviving oligodendrocytes and invading Schwann cells after the 15 th day. On the other hand, diabetic rats that received PPF presented lesions similar to those of non-diabetic animals, with rapid remyelination at the edges of the lesion site and fast clearance of myelin debris from the central area. Conclusion: The administration of PPF apparently reversed the impairment in remyelination induced by the diabetic state. Arch Endocrinol Metab. 2015;59(1):47-53

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“…Increased level of TNF-␣ in brain tissue has been found in cerebral ischemia (Lavine et al, 1998), causing neuronal cell death via induction of free radicals in glial cells (Hu et al, 1997) and apoptosis (Böhler et al, 2000). Recently, cyclic AMP elevating agents such as Ro-201724, amrinone, milrinone, and pentoxyphylline inhibited TNF-␣ production in rat hearts and glial cells (Yoshikawa et al, 1999). The ROS including H 2 O 2 and its derived form, hydroxyl radical (Li et al, 1997), are implicated in the signaling pathways initiated by TNF-␣, which is in turn involved in apoptosis (Kroemer et al, 1995;Böhler et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Cilostazol against Focal Cerebral Ischemia via Antiapoptotic Action in Rats

Choi¹,

Shin²,

Kim³

et al. 2002

J Pharmacol Exp Ther

135

100

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This study examined the protective effects of cilostazol on cerebral infarcts produced by subjecting rats to 2-h occlusion of the left middle cerebral artery followed by 24-h reperfusion. The ischemic cerebral infarct consistently involved the cortex and striatum. The infarct size was significantly reduced, when rats received 10 mg/kg cilostazol intravenously 5 min or 1 h after the completion of 2-h ischemia. Cyclic AMP level was significantly elevated in the cortex of 4-and 12-h reperfusion (P Ͻ 0.01) following treatment with cilostazol (10 mg/kg, 5 min after 2-h ischemia) accompanied by decreased tumor necrosis factor-␣ level. Samples from the regions corresponding to the penumbra showed markedly reduced Bcl-2 protein level and, in contrast, high levels of Bax protein and cytochrome c release. Cilostazol decreased Bax protein and cytochrome c release and increased the levels of Bcl-2 protein. Cilostazol (10

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Effects of phosphodiesterase inhibitors on cytokine production by microglia

Cited by 10 publications

References 0 publications

Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia

Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia

Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats

Neuroprotective Effect of Cilostazol against Focal Cerebral Ischemia via Antiapoptotic Action in Rats

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