Vinpocetine’s immunomodulating, anti-oxidant, anti-inflammatory, ant-ifibrotic, and PDE inhibiting potencies ameliorate bleomycin-induced pulmonary fibrosis

Document Type : Original Article


1 Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia

2 Pharmacology Department, Faculty of Medicine, Tanta University, El-Gish Street, Postal No. 31527, Tanta, Egypt

3 Histology Department, Faculty of Medicine, Tanta University, El-Gish Street, Postal No. 31527 Tanta, Egypt

4 Department of Pharmacy, University G. d’Annunzio, Chieti-Pescara, Italy

5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Postal No. 33516, Kafr El Sheikh, Egypt


Objective(s): Pulmonary fibrosis (PF) is a global health problem with a high economic burden. Intratracheal administration of bleomycin is the best model that resembles the pathogenesis of PF in humans. Recently, vinpocetine proved to have neuroprotective, cardioprotective, hepatoprotective, anti-aging, and antifibrotic effects through its anti-oxidant, immunomodulating, and anti-inflammatory activities. The present study investigated the antifibrotic potentiality of vinpocetine in a rat model of PF induced by intratracheal bleomycin administration. 
Materials and Methods: PF induced by a single intratracheal instillation of 5 mg/kg bleomycin in nine-week-old Wister rats. Oral vinpocetine was used at doses of 5, 10, or 20 mg/kg to treat PF for 21 days immediately after the bleomycin instillation. 
Results: Vinpocetine dose-dependently ameliorates PF induced by bleomycin administration since vinpocetine effectively restored the normal body weight gain rates, pulmonary architecture, and collagen fiber distribution and suppressed the elevated BALF cell count, lymphocytes and neutrophils percentage, BALF, IL-6, TNF-α, and TGF-β1 levels and LDH activity, lung tissue MDA level, PDE activity, hydroxyproline content, immunohistochemical expression of α-SMA and CD68 positive macrophage, and fibrosis score. Meanwhile, it efficiently augmented the reduced BALF macrophage percentage, IL-10 level, lung tissue GSH level, CAT, and SOD activities. 
Conclusion: Vinpocetine may propose a new promising agent to manage PF.


1. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: Review of the literature. Eur Respir Rev 2012; 21:355-361.
2. Wang L, Li S, Yao Y, Yin W, Ye T. The role of natural products in the prevention and treatment of pulmonary fibrosis: A review. Food Func 2021;12:990-1007.
3. Zhang Y, Gu L, Xia Q, Tian L, Qi J, Cao M. Radix astragali and radix angelicae sinensis in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Front Pharmacol 2020; 11:415.
4. Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci 2021; 78:2031-2057.
5. Huang Y-Y, Deng J, Tian Y-J, Liang J, Xie X, Huang Y, et al. Mangostanin derivatives as novel and orally active phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis with improved safety. J Med Chem 2021;64:13736-13751.
6. Kseibati MO, Shehatou GS, Sharawy MH, Eladl AE, Salem HA. Nicorandil ameliorates bleomycin-induced pulmonary fibrosis in rats through modulating eNOS, iNOS, TXNIP and HIF-1α levels. Life Sci 2020; 246:117423.
7. Chen R-r, Li Y-j, Chen J-j, Lu C-l. A review for natural polysaccharides with anti-pulmonary fibrosis properties, which may benefit to patients infected by 2019-nCoV. Carbohydr Polym 2020;247:116740.
8. Elnfarawy AA, Nashy AE, Abozaid AM, Komber IF, Elweshahy RH, Abdelrahman RS. Vinpocetine attenuates thioacetamide-induced liver fibrosis in rats. Hum Exp Toxicol 2021; 40:355-368.
9. Xu M, Li S, Wang J, Huang S, Zhang A, Zhang Y, et al. Cilomilast ameliorates renal tubulointerstitial fibrosis by inhibiting the TGF-β1-Smad2/3 signaling pathway. Front Med 2021; 7:626140.
10. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214:199-210.
11. Wu Y, Tian Y-J, Le M-L, Zhang S-R, Zhang C, Huang M-X, et al. Discovery of novel selective and orally bioavailable phosphodiesterase-1 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis. J Med Chem 2020; 63:7867-7879.
12. Dubey A, Kumar N, Mishra A, Singh Y, Tiwari M. Review on vinpocetine. Int J Pharm Life Sci 2020; 11: 6590-6597.
13. Nadeem RI, Ahmed HI, El-Sayeh BM. Protective effect of vinpocetine against neurotoxicity of manganese in adult male rats. Naunyn Schmiedeberg Arch Pharmacol 2018; 391:729-742.
14. Zhang C, Yan C. Updates of recent vinpocetine research in treating cardiovascular diseases. J Cell Immunol 2020; 2:211.
15. Poursalehi HR, Fekri MS, Far FS, Mandegari A, Izadi A, Mahmoodi R, et al. Early and late preventive effect of Nigella sativa on the bleomycin-induced pulmonary fibrosis in rats: An experimental study. Avicenna J Phytomed 2018; 8:263.
16. Balaha M, Ahmed N, Geddawy A, Kandeel S. Fraxetin prevented sodium fluoride-induced chronic pancreatitis in rats: Role of anti-inflammatory, antioxidant, antifibrotic and anti-apoptotic activities. Int Immunopharmacol 2021; 93:107372.
17. Balaha MF, Tanaka H, Yamashita H, Abdel Rahman MN, Inagaki N. Oral Nigella sativa oil ameliorates ovalbumin-induced bronchial asthma in mice. Int Immunopharmacol 2012; 14:224-231.
18. Pesce AJ. Lactate dehydrogenase. In; Methods  in  Clinical  Chemistry. 1st ed. Mosby Book: St  Louis; 1987. p. 903–906.
19. Gornall AG, Bardawill CJ, David MM. Determination of serum proteins by means of the biuret reaction. J Biol Chem 1949; 177:751-766.
20. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82:70-77.
21. Nishikimi M, Rao NA, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 1972; 46:849-854.
22. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351-358.
23. Aebi H. Catalase in vitro. Methods Enzymol 1984; 105:121-126.
24. Reddy GK, Enwemeka CS. A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem 1996; 29:225-229.
25. Suvarna KS, Layton C, Bancroft JD. Bancroft’s theory and practice of histological techniques E-Book: Elsevier Health Sciences; 2018.
26. Hübner R-H, Gitter W, Eddine El Mokhtari N, Mathiak M, Both M, Bolte H, et al. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 2008; 44:507-517.
27. Gagnon L, Leduc M, Grouix B, Tremblay M, Sarra-Bournet F, Laverdure A, et al. C74 models and methods in lung biology: Oral treatment with Pbi-4050 reduces plasminogen activator inhibitor-1 (pai-1), alpha-smooth muscle actin ([alpha]-sma) and collagen expression in human fibroblasts and mice fibrotic lungs. Am J Respir Crit Care Med 2016; 193:1.
28. Matsuyama S, Karim MR, Izawa T, Kuwamura M, Yamate J. Immunohistochemical analyses of the kinetics and distribution of macrophages in the developing rat kidney. J Toxicol Pathol 2018;31:207-212.
29. Pereira T, Naik S, Tamgadge A. Quantitative evaluation of macrophage expression using CD68 in oral submucous fibrosis: an immunohistochemical study. Ann Medical Health Sci Res 2015; 5:435-441.
30. Yanagihara T, Chong SG, Vierhout M, Hirota JA, Ask K, Kolb M. Current models of pulmonary fibrosis for future drug discovery efforts. Expert Opin Drug Discov 2020; 15:931-941.
31. Kolb P, Upagupta C, Vierhout M, Ayaub E, Bellaye PS, Gauldie J, et al. The importance of interventional timing in the bleomycin model of pulmonary fibrosis. Eur Respir J 2020; 55 :1901105.
32. Kaul S, Kaur I, Jakhar D, Edigin E, Caldito EG. The diverse methods of bleomycin delivery in cutaneous warts: A literature review. Dermatol Ther 2021; 34:e14401.
33. Jenkins RG, Moore BB, Chambers RC, Eickelberg O, Königshoff M, Kolb M, et al. An official American Thoracic Society workshop report: Use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. Am J Respir Cell  Mol Biol 2017; 56:667-679.
34. Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. A J Physiol Lung Cell Mol Physiol 2008; 294:L152-L160.
35. Izbicki G, Segel M, Christensen T, Conner M, Breuer R. Time course of bleomycin‐induced lung fibrosis. Int J Exp Pathol 2002; 83:111-119.
36. Tavares LA, Rezende AA, Santos JL, Estevam CS, Silva AM, Schneider JK, et al. Cymbopogon winterianus essential oil attenuates bleomycin-induced pulmonary fibrosis in a murine model. Pharmaceutics 2021;13:679.
37. Dias HB, de Oliveira JR, Donadio MVF, Kimura S. Fructose-1, 6-bisphosphate prevents pulmonary fibrosis by regulating extracellular matrix deposition and inducing phenotype reversal of lung myofibroblasts. PloS One 2019; 14:e0222202.
38. Nekrassov V, Sitges Ma. Vinpocetine protects from aminoglycoside antibiotic-induced hearing loss in guinea pig in vivo. Brain Res 2000; 868:222-229.
39. Kseibati MO, Sharawy MH, Salem HA. Chrysin mitigates bleomycin-induced pulmonary fibrosis in rats through regulating inflammation, oxidative stress, and hypoxia. Int Immunopharmacol 2020; 89:107011.
40. Hosseini SA, Zahedipour F, Sathyapalan T, Jamialahmadi T, Sahebkar A. Pulmonary fibrosis: Therapeutic and mechanistic insights into the role of phytochemicals. BioFactors 2021;47:250-269.
41. Huai B, Ding J. Atractylenolide III attenuates bleomycin-induced experimental pulmonary fibrosis and oxidative stress in rat model via Nrf2/NQO1/HO-1 pathway activation. Immunopharmacol Immunotoxicol 2020; 42:436-444.
42. Luhach K, Kulkarni GT, Singh VP, Sharma B. Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress. Autism Res 2021;14:2270-2286.
43. Ren L, Yang C, Dou Y, Zhan R, Sun Y, Yu Y. MiR-541-5p regulates lung fibrosis by targeting cyclic nucleotide phosphodiesterase 1A. Exp Lung Res 2017; 43:249-258.
44. Essam RM, Ahmed LA, Abdelsalam RM, El-Khatib AS. 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.