Research Area
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Description
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Neurological Disease |
Biological Activity
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Description
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S-(+)-Rolipram inhibits human monocyte cyclic AMP-specific PDE4 with IC50 of 0.75 μM. |
Targets
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PDE4 |
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IC50 |
750 nM [1] |
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In Vitro
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S-(+)-Rolipram suppresses LPS-induced TNFα expression from human monocyte through inhibiting PDE4 with IC50 about 2 μM. [1] 1 μM S-(+)-Rolipram significantly antagonizes ovalbumin (OA) induced concentration-related contractions of tracheal rings which are isolated from OA-sensitized guinea pigs. [2] S-(+)-Rolipram inhibits PDE4 activity in a CHO-K1 cell line which stably expresses a recombinant full length human PDE-4a with IC50 at 450 nM. [3] Treatment of the human glioma cell line A-172 with Rolipram (including both R- and S-enantiomers of Rolipram) results in increased expression of the cell cycle inhibitors p21 [Cip1] and p27 [Kip1], and decreased activity of cdk2, a cyclindependent kinase essential for cell cycle progression. As a result, the proliferation of A-172 cells is inhibited, with induction of a G1 block. Eventually, Rolipram-treated A-172 cells undergo differentiation, which is followed by apoptotic cell death. [4] |
In Vivo
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In anesthetized, ventilated OA-sensitive guinea pigs, S-(+)-Rolipram reduces OA-induced bronchoconstriction with ID50 values of approximately 0.25 mg/kg i.v. Histamine- and leukotriene D4-induced bronchoconstriction are not affected by doses of S-(+)-Rolipram which abolishes the response to OA. Higher doses (3-10 mg/kg) reduce histamine-, but not the leukotriene D4-induced bronchoconstriction. In conscious OA-sensitive guinea pigs, intragastric pretreatment with S-(+)-Rolipram dose-dependently reduces both the OA-induced decreases in specific conductance as well as the corresponding pulmonary eosinophil influx as assessed by both bronchoalveolar lavage and histological evaluation. [2] |
Clinical Trials
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Rolipram (including both R- and S-enantiomers of Rolipram) is under the Phase I clinical trial for its antidepressant effects on cAMP specific phosphodiesterase (PDE4) in depressed patients. |
Features
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Protocol
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Kinase Assay
[1]
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PDE Assay |
PDE activity is determined by the two-step radioisotope method of Thompson et al (1979). The reaction mixture contains: Tris-HCl 20 mM (pH 8.0), MgCl2 10 mM, 2-mercaptoethanol 4 mM, ethyleneglycol-bis-(f-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) 0.2 mM, bovine serum albumin, 0.05 mg/mL. Unless otherwise stated, the substrate concentration is 1 μM. The IC50 values (concentration which produced 50% inhibition of substrate hydrolysis) for the compounds are determined from concentration (0.1 nM to 40 μM)-response curves. At least three concentration-response curves are generated for each agent. |
Animal Study
[2]
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Animal Models |
Male Hartley guinea pigs |
Formulation |
S-(+)-Rolipram is dissolved in 100% PEG at an appropriate concentration. |
Doses |
1 mL/kg |
Administration |
Administered via i.v. |
References |
[1] Souness JE, et al. Br J Pharmacol, 1996, 118(3), 649-658
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[2] Underwood DC, et al. J Pharmacol Exp Ther, 1993, 266(1), 306-313
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[3] Pon DJ, et al. Cell Biochem Biophys, 1998, 29(1-2), 159-178.
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[4] Chen TC, et al. Cancer Biol Ther, 2002, 1(3), 268-276.
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