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Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways.
Life Sci. 2019 Apr 01; 222:245-254.LS

Abstract

BACKGROUND

Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis.

AIM

The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats.

MAIN METHODS

Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks.

KEY FINDINGS

Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-β1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine.

SIGNIFICANCE

Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.

Authors+Show Affiliations

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: reham.essam@pharma.cu.edu.eg.Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: lamiaa.ahmed@pharma.cu.edu.eg.Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: rania.mohsen@pharma.cu.edu.eg.Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: aiman.elkhatib@pharma.cu.edu.eg.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30858122

Citation

Essam, Reham M., et al. "Phosphodiestrase-1 and 4 Inhibitors Ameliorate Liver Fibrosis in Rats: Modulation of cAMP/CREB/TLR4 Inflammatory and Fibrogenic Pathways." Life Sciences, vol. 222, 2019, pp. 245-254.
Essam RM, Ahmed LA, Abdelsalam RM, et al. Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways. Life Sci. 2019;222:245-254.
Essam, R. M., Ahmed, L. A., Abdelsalam, R. M., & El-Khatib, A. S. (2019). Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways. Life Sciences, 222, 245-254. https://doi.org/10.1016/j.lfs.2019.03.014
Essam RM, et al. Phosphodiestrase-1 and 4 Inhibitors Ameliorate Liver Fibrosis in Rats: Modulation of cAMP/CREB/TLR4 Inflammatory and Fibrogenic Pathways. Life Sci. 2019 Apr 1;222:245-254. PubMed PMID: 30858122.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways. AU - Essam,Reham M, AU - Ahmed,Lamiaa A, AU - Abdelsalam,Rania M, AU - El-Khatib,Aiman S, Y1 - 2019/03/08/ PY - 2018/12/25/received PY - 2019/03/07/revised PY - 2019/03/07/accepted PY - 2019/3/13/pubmed PY - 2019/3/29/medline PY - 2019/3/13/entrez KW - Diethylnitrosamine KW - Hepatic fibrosis KW - Phosphodiesterase inhibitors KW - Roflumilast KW - Vinpocetine SP - 245 EP - 254 JF - Life sciences JO - Life Sci. VL - 222 N2 - BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-β1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/30858122/Phosphodiestrase_1_and_4_inhibitors_ameliorate_liver_fibrosis_in_rats:_Modulation_of_cAMP/CREB/TLR4_inflammatory_and_fibrogenic_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(19)30172-9 DB - PRIME DP - Unbound Medicine ER -