Rolipram

Rolipram is a PDE4-inhibitor and an anti-inflammatory agent.

PDE4 Inhibition by Rolipram Promotes Neuronal Differentiation in Human Bone Marrow Mesenchymal Stem Cells.[Pubmed:27459581]

Cell Reprogram. 2016 Aug;18(4):224-9.

Increased intracellular cyclic adenosine monophosphate (cAMP) can promote axonal elongation and facilitate neuronal repair, while decreased cAMP is associated with losses in neuronal regenerative capacity. Rolipram, which upregulates intracellular cAMP by blocking phosphodiesterase-4 (PDE4) enzyme activity, can mitigate diverse neurological disorders. In this study, we investigated whether Rolipram induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). Rolipram-treated MSCs (Roli-MSCs) had significantly increased expression of the neuroprogenitor proteins Nestin, Musashi, GFAP, and Sox-2. When Roli-MSCs were differentiated with neuronal induction media (Roli-dMSCs), they exhibited cell body and dendritic morphologies similar to those of neurons. The neurite number and length of Roli-dMSCs were significantly increased compared to those of differentiated MSCs (dMSCs). Compared with undifferentiated hBM-MSCs, the Roli-dMSCs and dMSCs showed significantly increased expression of the neuronal-specific marker genes Nestin, Musashi, CD133, GFAP, NF-M, MAP-2, KCNH1, KCNH5, SCN3A, and CACNA1A, and decreased expression of other lineage-specific markers Adiponectin, ALP, FABP4, and MMP13. The Roli-dMSCs also showed a higher expression of the neuronal markers Nestin, Musashi, Sox-2, NF-M, and Tuj-1 compared to those of the undifferentiated hBM-MSCs, measured by immunocytochemistry and immunoblotting assay. Thus, we have shown that Rolipram ameliorates neuronal differentiation by the regulation of neuroprogenitor expression in hBM-MSCs, and Rolipram treatment of MSCs may improve the therapeutic efficacy of stem cell therapy for neurodegenerative disorders.

The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells.[Pubmed:27143817]

Mediators Inflamm. 2016;2016:3745961.

Exposure to bacterial lipopolysaccharides (LPS) induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4) inhibitor Rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca(2+) signaling in salivary acinar and ductal cells. Submandibular gland (SMG) expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca(2+) signaling and ROS production in SMG. Treatment with Rolipram blocked LPS-induced Ca(2+) increase and ROS production. The application of histamine evoked Ca(2+) signals and ROS production, which were attenuated by Rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by Rolipram. The inhibitory role of Rolipram in ROS-induced Ca(2+) signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca(2+) signals were upregulated by the treatment of Rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by Rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells.

Rolipram potentiates bevacizumab-induced cell death in human glioblastoma stem-like cells.[Pubmed:28202289]

Life Sci. 2017 Mar 15;173:11-19.

AIMS: Glioblastoma cancer stem-like cells (GCSCs) promote themselves proliferation by secreting the vascular endothelial growth factor A (VEGFA) in an autocrine manner, positively regulated by phosphodiesterase IV (PDE4). In the current study, we investigated the putative cytotoxic effect of bevacizumab, a VEGFA blocker, alone and in combination with a specific inhibitor of PDE4 called Rolipram on GCSCs isolated from human surgical tumor specimen with a focus on PI3K/AKT pathway. MAIN METHODS: CD133+/CD15+ GCSCs were characterized by flow cytometry and expanded in a serum-free primary culture system. The cell survival, apoptosis, and protein expression values were measured using MTT assay, TUNEL staining and western blot, successively. Intracellular cAMP and free secreted VEGFA levels were assessed by cAMP enzyme immunoassay and ELISA, respectively. KEY FINDINGS: Bevacizumab suppressed GCSCs survival with IC50~6.5mug/ml and enhanced the levels of apoptosis, p53 and cleaved-caspase3 along with a decrease in free VEGFA levels and ERKs activation. However, there was no significant modulation of AKT phosphorylation on serine 473, the intracellular PDE4A, VEGFA and cAMP levels. More cytotoxicity in co-treated cells coupled with a more substantial decline in the free VEGFA levels and a greater increase in the quantities of p53 and cleaved-caspase3 compared to those treated with bevacizumab alone. Co-treatment reduced phospho-AKT, endogenous VEGFA and PDE4A values but elevated cAMP levels. SIGNIFICANCE: This study highlighted a booster cytotoxic effect of combined Rolipram and bevacizumab treatment on the GCSCs primary culture, suggesting that this approach is warranted in treatment of GBMs overexpressing VEGFA and PDE4A.

The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain.[Pubmed:28025994]

Int J Mol Med. 2016 Nov;38(5):1433-1442.

Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal 'neuron-astrocytic' activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti-inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL. The analgesic effects of ROL were evaluated using the Von Frey and Hargreaves tests. Immunofluorescence staining was used to determine the number of c-Fos immunoreactive neurons, and the expression of spinal astrocytes and microglial activation on day 14 after tumor cell inoculation. Enzymelinked immunosorbent assay (ELISA) was used to detect the expression of pro-inflammatory cytokines [interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] and chemokines (CCL2), and western blot analysis was then used to examine the spinal phosphodiesterase 4 (PDE4), ionized calcium binding adapter molecule-1 (IBA-1) and JNK levels on day 14 after tumor cell inoculation. The results revealed that ROL exerted a short-term analgesic effect in a dose-dependent manner, and consecutive daily injections of ROL exerted continuous analgesic effects. In addition, spinal 'neuronastrocytic' activation was suppressed and was associated with the downregulation of spinal IL-1beta, IL-6 and TNF-alpha expression, and the inhibition of PDE4B and JNK levels in the spine was also observed. In addition, the level of CCL2 was decreased in the rats with BCP. The JNK inhibitor, SP600125, decreased CCL2 expression and attenuated pain behavior. Following co-treatment with ROL and SP600125, no significant increases in thermal hyperalgesia and CCL2 expression were observed compared with the ROL group. Thus, our findings suggest that the analgesic effects of ROL in BCP are mainly mediated through the inhibition of 'neuronastrocytic' activation, which occurs via the suppression of spinal JNK/CCL2 signaling.

Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future?[Pubmed:9184477]

Trends Pharmacol Sci. 1997 May;18(5):164-71.

Phosphodiesterase type 4 (PDE4) plays a major role in modulating the activity of virtually all cells involved in the inflammatory process. Inhibitors of this enzyme family display impressive anti-inflammatory and disease-modifying effects in a variety of experimental models. In this review, Mauro Teixeira, Robert Gristwood, Nicola Cooper and Paul Hellewell examine the capacity of PDE4 inhibitors to exert anti-inflammatory actions in vivo and discuss the potential of this class of drugs to take their place as novel therapeutic agents for a variety of inflammatory diseases.

Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, reduces neuronal damage following cerebral ischemia in the gerbil.[Pubmed:7713141]

Eur J Pharmacol. 1995 Jan 5;272(1):107-10.

We examined the effects of Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, on cerebral ischemia-induced neuronal damage in Mongolian gerbils. Transient forebrain ischemia was induced by 3-min occlusion of bilateral common carotid arteries. Rolipram, at a dose of 0.3 or 3 mg/kg, was injected i.p. 30 min before ischemia. Histopathological observations showed that neuronal damage to the hippocampal CA1 subfield, which was seen 7 days after ischemia in vehicle-treated animals, was reduced in animals treated with the higher dose of Rolipram.

Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate.[Pubmed:8383740]

J Pharmacol Exp Ther. 1993 Mar;264(3):1168-78.

Four inhibitors of cyclic AMP phosphodiesterase (PDE), Rolipram, Ro 20-1724, ICI 63,197 and CP 76,593, reduced response rates and increased reinforcement rates of rats under a differential reinforcement of low rate 72-sec schedule for water reinforcement in a dose-dependent manner. These actions of the PDE inhibitors are similar to those reported for proven antidepressant drugs. Administration of forskolin, which increases cyclic AMP levels by activation of the catalytic subunit of adenylyl cyclase, either i.p. or i.c.v. did not mimic the effects of the PDE inhibitors. The behavioral effects of the PDE inhibitors were not antagonized by the beta adrenergic antagonist propranolol, suggesting that these drugs were not altering behavior via an increase in norepinephrine release and an indirect stimulation of beta adrenergic receptors. 6-Hydroxydopamine-induced lesions of noradrenergic neurons increased sensitivity to Rolipram. This suggests that alterations in PDE activity with a concomitant increase in sensitivity to PDE inhibitors may occur subsequent to functional denervation.

Rolipram is a selective phosphodiesterases PDE4 inhibitor with IC50s of 3 nM, 130 nM and 240 nM for PDE4A, PDE4B, and PDE4D, respectively.

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