cAMP is a fundamental second-messenger molecule produced in essentially all mammalian cells. 3′5′-Cyclic nucleotide phosphodiesterases (PDEs) are the enzymatic machinery that is responsible for the degradation of cAMP in cells by catalysing the hydrolysis of cAMP to 5′AMP. PDE4 family members specifically degrade cAMP, and they are expressed essentially in all immune cells including macrophages, neutrophils, eosinophils and lymphocytes, and in many other cell types, including epithelial cells, endothelium and fibroblasts. Rolipram is a selective inhibitor of phosphodiesterase PDE4, especially the PDE4B with IC50 of 130 nM and IC50 of 240 nM for PDE4D, with anti-inflammatory activity. Transient global cerebral ischemia in rats was induced by BCCAO. Rolipram at 0.3 mg/kg, but not 0.1 mg/kg, increased the time spent in the open arms and Discrimination index in the object location task, and the number of DCX-immunoreactive (DCX is a microtubule protein transiently expressed in both cytoplasm and dendrites of newborn neurons) neurons in BCCAO mice as compared to the BCCAO + veh group[3]. Bevacizumab (6.5 μg/ml) and rolipram (103 μM) individually led to the significant increase in the relative values of p53 and cleaved-caspase3 expressions in glioblastoma cancer stem-like cells (GCSCs) and the effect was strongly amplified when bevacizumab and rolipram were added to culture medium simultaneously[4]. Rolipram inhibited LPS-induced TNF production and TNF mRNA levelsin a dose-dependent manner (IC50 25.9 nM) in J774 mouse macrophages, which was mediated by MAPK phosphatase-1 (MKP-1)[5].
Rolipram/咯利普兰 细胞实验
Cell Line
Concentration
Treated Time
Description
References
J774 mouse macrophage cell line
2 µM
1 hour
Rolipram enhanced LPS-induced MKP-1 mRNA and protein expression and inhibited p38 MAPK phosphorylation.
To investigate the effect of Rolipram on PAF- and C5a-stimulated LTC4 synthesis in human eosinophils, results showed that Rolipram significantly inhibited LTC4 synthesis.
Br J Pharmacol. 1996 Aug;118(7):1727-35.
DRG neurons
0.1, 0.25, 0.5, 1.0, and 2.0 µM
18 hours
Rolipram overcame inhibition by both MAG and myelin in a dose-dependent manner, completely blocking inhibition by MAG at 0.5 µM.
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8786-90.
CHO cells
0.1, 0.25, 0.5, 1.0, and 2.0 µM
18 hours
Rolipram overcame inhibition by both MAG and myelin in a dose-dependent manner, completely blocking inhibition by MAG at 0.5 µM.
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8786-90.
To evaluate the cytotoxic effect of NEO214 on U251 cells, results showed that NEO214 was cytotoxic to both TMZ-sensitive and TMZ-resistant glioma cells.
Autophagy. 2023 Dec;19(12):3169-3188.
U251TR cells
100 µM
48 hours
To evaluate the cytotoxic effect of NEO214 on U251TR cells, results showed that NEO214 was cytotoxic to both TMZ-sensitive and TMZ-resistant glioma cells.
Autophagy. 2023 Dec;19(12):3169-3188.
T98G cells
100 µM
48 hours
To evaluate the cytotoxic effect of NEO214 on T98G cells, results showed that NEO214 was cytotoxic to both TMZ-sensitive and TMZ-resistant glioma cells.
Autophagy. 2023 Dec;19(12):3169-3188.
Rat mixed neural cell myelinating cultures
10 nM–10 µM
7 days
Rolipram enhanced neurite density in areas closely surrounding the lesion and induced significant neurite outgrowth across the lesion over a broad concentration range of 10 nM–10 μM. Rolipram enhanced myelination surrounding the lesion at a concentration range of 10–50 nM, but inhibited myelination at higher concentrations.
Br J Pharmacol. 2014 May;171(9):2385-98.
oligodendrocyte progenitor cells (OPCs)
0.5 µM
48 h
rolipram promotes OPC differentiation in the presence of myelin-associated inhibitors, increasing O4 and Mbp expression
EMBO Mol Med. 2013 Dec;5(12):1918-34
Rolipram/咯利普兰 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
ICR mice
Antidepressant- and anxiolytic-like behavior model
Intraperitoneal injection
0.31, 0.62, 1.25 mg/kg
Once daily for 17-23 days
Rolipram produced antidepressant- and anxiolytic-like effects on behavior by increasing cAMP and pCREB levels in the hippocampus and prefrontal cortex, and increasing Sox2 expression in the hippocampus.
Neuropsychopharmacology. 2009 Oct;34(11):2404-19
Long Evan Hooded rats
Spinal cord hemisection model
Subcutaneous injection
0.4 or 0.8 µmol/kg per hour
Continuous for 10 days
Rolipram significantly promoted axon regeneration, attenuated the formation of the glial scar, and significantly enhanced functional recovery.
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8786-90.
Sprague- Dawley rats
Conscious and anesthetized rats
Intravenous infusion
0–1 mg/kg
60 minutes
To measure the binding site density (B max) and radioligand affinity (1/K D) of 11C-(R)-rolipram in the rat brain, and to study the differences in binding between conscious and anesthetized states. Results showed that B max and K D were significantly higher in conscious rats compared to anesthetized rats, and the in vitro K D was 3–7 times greater than the in vivo K D.
J Nucl Med. 2009 May;50(5):749-56
C57BL/6 mice
Carrageenan-induced paw inflammation model
Intraperitoneal injection
100 mg/kg
Single dose, 3 hours duration
Rolipram significantly attenuated carrageenan-induced paw inflammation in WT mice but had no significant effect in MKP-1(–/–) mice.
Br J Pharmacol. 2013 Aug;169(7):1525-36.
Sprague- Dawley rats
Bone cancer pain model
Intrathecal injection
12.5, 25, 50, 100 µg/kg
Daily injection for 7 days
Rolipram significantly alleviated mechanical allodynia and thermal hyperalgesia in rats with bone cancer pain by inhibiting the spinal JNK/CCL2 signaling pathway and astrocytic activation
Int J Mol Med. 2016 Nov;38(5):1433-1442
BALB/c mice
LPS-induced lung inflammation model
Intraperitoneal injection
20 mg/kg
Single injection, lasting 45 minutes
To investigate the effect of Rolipram on LPS-induced lung inflammation, the results showed that Rolipram significantly reduced TNF-α levels in the BALF and almost completely inhibited LPS-induced neutrophil infiltration.
Br J Pharmacol. 1998 Feb;123(4):631-6
Athymic rats
C5 hemisection model
Local delivery
25 µg/ml, 500 µg/ml
Single administration, lasted for 8 weeks
To evaluate the functional and anatomical recovery effects of Rolipram on spinal cord injury repair. Low-dose Rolipram significantly improved functional and anatomical recovery, while high-dose Rolipram was similar to the untreated group and resulted in reduced animal survival rates.
J Control Release. 2012 Aug 10;161(3):910-7
C57BL/6J mice
CCl4-induced liver fibrosis model
Targeted hepatic delivery
3.3 mg/kg
24 hours after each CCl4 administration, for 4 weeks
Administered 24 and 2 hours prior to infection and daily thereafter
To assess the effects of rolipram on the antibacterial host response in mice infected with Klebsiella pneumoniae. Results showed that rolipram treatment was associated with earlier lethality and significant inhibition of TNF-α production, along with enhanced IL-10 production in lung tissue. Rolipram treatment did not affect KC expression and neutrophil recruitment in lung tissue but inhibited neutrophil phagocytosis of K. pneumoniae.
Br J Pharmacol. 2003 Nov;140(5):855-62
Nude mice
Intracranial glioma model
Subcutaneous injection
50 mg/kg
30 days, 5 days on, 2 days off
To evaluate the anti-tumor effect of NEO214 in an intracranial glioma model, results showed that NEO214 significantly delayed tumor growth and prolonged the survival of mice.
Autophagy. 2023 Dec;19(12):3169-3188.
Sprague- Dawley rats
Acute inflammation model
Intraperitoneal injection
8 mg/kg
Single dose, 30 minutes before the experiment
Rolipram significantly inhibited PAF and LPS-induced leukocyte rolling, adhesion, and emigration by 100%, 95%, and 95%, respectively. Additionally, Rolipram reversed the decrease in leukocyte rolling velocity induced by PAF.
United States, Maryland
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National Institutes of Health Clinical Center
Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov 收起 <<
Inhibition of PDE4B2 expressed in COS7 cells assessed as cAMP hydrolysis, IC50=0.105 μM
18222088
HEK293 cells
Function assay
Inhibition of PDE4 expressed in HEK293 cells coexpressing G-protein coupled receptor and cyclic nucleotide gated ion channel by fluorescence assay, EC50=0.1315 μM
19464886
human PBMC
Function assay
Inhibition of LPS-induced TNFalpha production in human PBMC, IC50=0.06 μM
19049349
human U937 cells
Function assay
Inhibition of PDE4 in human U937 cells assessed as accumulation of [3H]adenosine by scintillation counting, IC50=0.86 μM
19303290
rat UMR106 cells
Function assay
Inhibition of PDE in rat UMR106 cells co-expressing CRE-luc assessed as PTH-induced cAMP accumulation by luciferase reporter gene assay, IC50=0.6 μM
22030030
Sf9 cells
Function assay
Inhibition of recombinant human PDE4A expressed in Sf9 cells, IC50=4 nM
United States, Maryland
... 展开 >>
National Institutes of Health Clinical Center
Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov 收起 <<
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