Disease relevance of rolipram

• The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials [1].
• The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis [1].
• We thus explored whether administration in vivo of the selective PDE-III antagonist, lixazinone (LX), together with the specific PDE-IV antagonist, rolipram (RP), can attenuate development of mesangioproliferative glomerulonephritis (MSGN) induced in rats by anti-rat thymocyte serum (ATS) [2].
• Unlike the vehicle-treated MSGN rats, rats with MSGN treated with LX and RP did not develop proteinuria and maintained normal renal function when examined 5 d after injection of ATS [2].
• Such hyperactivation was accomplished by recruiting the rolipram-sensitive cyclic nucleoside phosphodiesterase 4 and resulted in increased susceptibility to HIV-1 infection [3].

Psychiatry related information on rolipram

• One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment [4].
• Coadministration of rolipram (4 mg/kg IP) significantly attenuated the responses of locomotor activity, rearing and repetitive head movements to MAP (2,4 or 8 mg/kg IP) [5].
• The effects of rolipram, a selective cAMP phosphodiesterase inhibitor, on locomotor activity, rearing, and stereotyped behavior (sniffing, repetitive head movements) induced by methamphetamine (MAP) over 1 hour were investigated in rats [5].
• Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence [6].
• Preliminary results with rolipram in patients with endogenous depression seem to support this assumption [7].

High impact information on rolipram

• Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination [8].
• Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells [1].
• Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice [4].
• Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates [9].
• The phosphodiesterase (PDE) inhibitors motapizone (10(-4) M), rolipram (10(-6) M), and zardaverine (10(-8) M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H2O2-induced endothelial permeability when combined with 10(-6) M prostaglandin E1 [10].

Chemical compound and disease context of rolipram

• In a subset of CLL patients, B-cell lymphoma 2 (Bcl-2)-associated death promoter homolog (Bad), a proapoptotic Bcl-2 family member that when phosphorylated on specific serine residues is sequestered in the cytosol by 14-3-3, was dephosphorylated at Ser112 following rolipram/forskolin treatment of leukemic cells [11].
• The phosphodiesterase inhibitor rolipram did not cause vasodilation, but suppressed edema and potentiated the cAMP response to albuterol in cultured endothelial cells [12].
• Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily) [13].
• Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p < 0.05) compared with non-iso/roli-reperfused groups after 2 h of postmortem ischemia [14].
• The transcriptional ability of a luciferase reporter gene under control of the HIV long terminal repeat, induced by phorbol myristic acetate plus ionomycin or by TNF-alpha, in primary T and Jurkat cells was also inhibited by rolipram [15].

Biological context of rolipram

• The PKA phosphorylation status of the beta(2)AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)AR [16].
• Rolipram/forskolin treatment augmented protein phosphatase 2A (PP2A) activity, as well as levels of immunoreactive PP2A catalytic subunit [11].
• In samples from 13 of 14 CLL patients, rolipram induced apoptosis in a dose-dependent fashion over a 48-hour period [17].
• Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465 [18].
• In addition to inhibiting the catalytic activity of PDE IV, rolipram binds to a high affinity binding site present in brain homogenates [19].

Anatomical context of rolipram

• The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery [20].
• Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes [21].
• We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo [20].
• Sensitivity to forskolin and rolipram is shared by at least 2 pediatric ALL cell lines, CEM and Reh cells [22].
• Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC) and anti-Ig stimulated CD19(+) B cells were resistant to the induction of apoptosis by rolipram while unstimulated CD19(+) B cells, which had a high basal apoptotic rate, were more sensitive [17].

Associations of rolipram with other chemical compounds

• We show that treatment of CLL cells with rolipram, a prototypic PDE4 inhibitor, and forskolin, an adenylate cyclase activator, induces mitochondrial depolarization, release of cytochrome c into the cytosol, caspase-9 and -3 activation, and cleavage of poly(adenosine diphosphate [ADP]-ribose)polymerase [11].
• The excitatory effects of intrathecally infused dibutyryl cAMP, 8-bromo cAMP, forskolin-DHA, or Rolipram support a functional link between spinal cord cAMP and the acoustic startle reflex [23].
• Transfection of COS7 cells with a plasmid encoding the human cyclic AMP-specific PDE4A phosphodiesterase PDE-46 (HSPDE4A4B) led to the expression of a rolipram-inhibited PDE4 activity, which contributed approximately 96% of the total COS cell PDE activity [24].
• Selective PDE IV inhibitors (rolipram and RO-20-1724), but not selective inhibitors of other types of PDE, significantly augment marcrophage IL-10 production and contribute to the inhibition of TNF-alpha and IL-6 release [25].
• Conversely, cilostamide or lixazinone suppressed mitogenic synthesis of DNA in mesangial cells, but 1 microM rolipram or 1 microM denbufylline showed no inhibitory effect [26].

Gene context of rolipram

• Accordingly, rolipram potently inhibited HIV-1 replication in cultures stimulated by anti-CD3/CD28 +/- Tat [3].
• Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia [27].
• Such an interaction profoundly changed the inhibition of PDE4 activity caused by the PDE4-selective inhibitor rolipram and mimicked the enhanced rolipram inhibition seen for particulate, compared with cytosolic pde46 expressed in COS7 cells [28].
• Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition [28].
• The selective PDE4 inhibitor rolipram increases AKAP-tethered PKA activity on AQP2-bearing vesicles and enhances the AQP2 shuttle and thereby the osmotic water permeability [29].

Analytical, diagnostic and therapeutic context of rolipram

• As anti-TNF-alpha therapy is effective in rheumatoid arthritis, we investigated the effect of rolipram on collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis [30].
• Northern blot analysis of spleens from these mice shows that rolipram increases IL-10 mRNA, whereas TNF-alpha mRNA remains largely unchanged [25].
• Most of the activity recovered in the immunoprecipitation pellets (90%) was inhibited by 10 microM Rolipram, an inhibitor specific for the high affinity cAMP-PDEs [31].
• Rolipram significantly (p < 0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5) [32].
• We have used an adherence-based protocol for separating peripheral blood mononuclear cells, isolated from atopic individuals, into lymphocyte and monocyte fractions and have selectively treated these populations with rolipram prior to reconstituting the cell cultures to their original lymphocyte/monocyte proportions [33].

References