Skip to main content

Advertisement

SpringerLink
Log in

Effects of tadalafil on ischemia/reperfusion injury in rat brain

  • Original Article
  • Published:
Acta Neurologica Belgica Aims and scope Submit manuscript

Abstract

Cerebral ischemia–reperfusion (I/R) injury is caused by lack of blood supply to the brain. The accumulation of toxic products such as reactive oxygen species (ROS) occurs on reperfusion, when the occlusion is removed. The resulting oxidative stress results in the initiation of pathways leading to necrotic and apoptotic cell death. Tadalafil (TAD) prevents the accumulation of ROS and increases antioxidant cellular protective mechanisms. The aim of this study was to investigate the effect of TAD treatment against short-term global brain I/R injury in rats. The study was carried out on 30 Wistar-albino rats, which were divided into three groups including a control group (n = 10), an I/R group (n = 10) and an I/R + TAD group (n = 10) (2 mg/kg/day for 4 days before ischemia). At the end of the experiment, tissue samples were collected for both biochemical and histopathological analyses. Malondialdehyde was significantly lower in the TAD-administered group (9.06 ± 0.15) than in the I/R group (p < 0.05). However, no significant difference was observed in nitric oxide levels in the TAD-administered group compared to the I/R group. The mean superoxide dismutase level was significantly higher in the I/R–TAD group than the I/R group. There was no statistically significant difference in glutathione peroxidase levels in I/R + TAD group compared to I/R group. Histopathologically, TAD-administered group provided significant morphological improvement compared to the I/R group. We concluded that TAD prevented I/R-induced neurotoxicity as shown by obtained biochemical and histopathological findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    Article  CAS  PubMed  Google Scholar 

  2. Leker RR, Shohami E (2002) Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Brain Res Rev 39:55–73

    Article  PubMed  Google Scholar 

  3. Benchoua A, Guegan C, Couriaud C, Hosseini H, Sampaio N, Morin D, Onteniente B (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21:7127–7134

    CAS  PubMed  Google Scholar 

  4. Lee JH, Lee YK, Ishikawa M, Koga K, Fukunaga M, Miyakoda G, Mori T, Hosokawa T, Hong KW (2003) Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats—an MRI study. Brain Res 994:91–98

    Article  CAS  PubMed  Google Scholar 

  5. Connell BJ, Saleh MC, Khan BV, Saleh TM (2011) Apocynin may limit total cell death following cerebral ischemia and reperfusion by enhancing apoptosis. Food Chem Toxicol 49:3063–3069

    Article  CAS  PubMed  Google Scholar 

  6. Chen YH, Du GH, Zhang JT (2000) Salvianolic acid B protects brain against injuries caused by ischemia–reperfusion in rats. Acta Pharmacol Sin 21:463–466

    CAS  PubMed  Google Scholar 

  7. Rodrigo J, Fernandez AP, Serrano J, Peinado MA, Martinez A (2005) The role of free radicals in cerebral hypoxia and ischemia. Free Radic Biol Med 39:26–50

    Article  CAS  PubMed  Google Scholar 

  8. Toyokuni S (1999) Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 49:91–102

    Article  CAS  PubMed  Google Scholar 

  9. Schmidley JW (1990) Free radicals in central nervous system ischemia. Stroke 21:1086–1090

    Article  CAS  PubMed  Google Scholar 

  10. Akyol O, Herken H, Uz E, Fadillioglu E, Unal S, Sogut S, Ozyurt H, Savas HA (2002) The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients: the possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol Biol Psychiatry 26:995–1005

    Article  CAS  PubMed  Google Scholar 

  11. Chan PH (1996) Role of oxidants in ischemic brain damage. Stroke 27:1124–1129

    Article  CAS  PubMed  Google Scholar 

  12. Zhang L, Zhang Z, Zhang RL, Cui Y, LaPointe MC, Silver B, Chopp M (2006) Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 1118:192–198

    Article  CAS  PubMed  Google Scholar 

  13. Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500

    CAS  PubMed  Google Scholar 

  14. Vignozzi L, Filippi S, Morelli A, Ambrosini S, Luconi M, Vannelli GB, Donati S, Crescioli C, Zhang XH, Mirone V, Forti G, Maggi M (2006) Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med 3:419–431

    Article  CAS  PubMed  Google Scholar 

  15. Ko IG, Shin MS, Kim BK, Kim SE, Sung YH, Kim TS, Shin MC, Cho HJ, Kim SC, Kim SH, Kim KH, Shin DH, Kim CJ (2009) Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. Pharmacol Biochem Behav 91:629–635

    Article  CAS  PubMed  Google Scholar 

  16. Ozdegirmenci O, Kucukozkan T, Akdag E, Topal T, Haberal A, Kayir H, Oter S, Akyol M, Uzbay T (2011) Effects of sildenafil and tadalafil on ischemia/reperfusion injury in fetal rat brain. J Matern Fetal Neonatal Med 24:317–323

    Article  CAS  PubMed  Google Scholar 

  17. Shi LL, Chen BN, Gao M, Zhang HA, Li YJ, Wang L, Du GH (2011) The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats. Life Sci 88:521–528

    Article  CAS  PubMed  Google Scholar 

  18. Nanri K, Montécot C, Springhetti V, Seylaz J, Pinard E (1998) The selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduces the delayed neuronal damage due to forebrain ischemia in rats. Stroke 29(6):1248–1253

    Article  CAS  PubMed  Google Scholar 

  19. Diaz-Ruiz A, Rios C, Duarte I, Correa D, Guizar-Sahagun G, Grijalva I, Madrazo I, Ibarra A (2000) Lipid peroxidation inhibition in spinal cord injury: cyclosporin-A vs methylprednisolone. NeuroReport 11:1765–1767

    Article  CAS  PubMed  Google Scholar 

  20. Kurt G, Ergun E, Cemil B, Borcek AO, Borcek P, Gulbahar O, Ceviker N (2009) Neuroprotective effects of infliximab in experimental spinal cord injury. Surg Neurol 71:332–336 (discussion 336)

    Google Scholar 

  21. Şahin Ş, Söğüt S, Özyurt H, Uz E, İlhan A, Akyol Ö (2002) Tissue xanthine oxidase activity and nitric oxide levels after spinal cord ischemia/reperfusion injury in rabbits: comparison of caffeic acid phenethyl ester (CAPE) and methylprednisolone. Neurosci Res Commun 31:111–121

    Article  Google Scholar 

  22. Ozerol E, Bilgic S, Iraz M, Cigli A, Ilhan A, Akyol O (2009) The protective effect of erdosteine on short-term global brain ischemia/reperfusion injury in rats. Prog Neuropsychopharmacol Biol Psychiatry 33(1):20–24

    Article  CAS  PubMed  Google Scholar 

  23. Gorgulu A, Kiris T, Unal F, Turkoglu U, Kucuk M, Cobanoglu S (2000) Superoxide dismutase activity and the effects of NBQX and CPP on lipid peroxidation in experimental spinal cord injury. Res Exp Med (Berl) 199:285–293

    Article  CAS  Google Scholar 

  24. van Driel MF (2006) Phosphodiesterase inhibitors: effectiveness and new applications. Ned Tijdschr Geneeskd 150:1613–1616 (abstract in English)

    Google Scholar 

  25. Corbin JD, Francis SH (2002) Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract 56:453–459

    CAS  PubMed  Google Scholar 

  26. Jeremy JY, Ballard SA, Naylor AM, Miller MA, Angelini GD (1997) Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br J Urol 79:958–963

    Article  CAS  PubMed  Google Scholar 

  27. Perk H, Armagan A, Naziroglu M, Soyupek S, Hoscan MB, Sutcu R, Ozorak A, Delibas N (2008) Sildenafil citrate as a phosphodiesterase inhibitor has an antioxidant effect in the blood of men. J Clin Pharm Ther 33:635–640

    Article  CAS  PubMed  Google Scholar 

  28. Keller JN, Hanni KB, Mattson MP, Markesbery WR (1998) Cyclic nucleotides attenuate lipid peroxidation-mediated neuron toxicity. NeuroReport 9:3731–3734

    Article  CAS  PubMed  Google Scholar 

  29. Guzeloglu M, Yalcinkaya F, Atmaca S, Bagriyanik A, Oktar S, Yuksel O, Fansa I, Hazan E (2011) The beneficial effects of tadalafil on renal ischemia–reperfusion injury in rats. Urol Int 86:197–203

    Article  CAS  PubMed  Google Scholar 

  30. Serarslan Y, Yonden Z, Ozgiray E, Oktar S, Guven EO, Sogut S, Yilmaz N, Yurtseven T (2010) Protective effects of tadalafil on experimental spinal cord injury in rats. J Clin Neurosci 17:349–352

    Article  PubMed  Google Scholar 

  31. Royl G, Balkaya M, Lehmann S, Lehnardt S, Stohlmann K, Lindauer U, Endres M, Dirnagl U, Meisel A (2009) Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. Brain Res 1265:148–157

    Article  CAS  PubMed  Google Scholar 

  32. Baek SB, Bahn G, Moon SJ, Lee J, Kim KH, Ko IG, Kim SE, Sung YH, Kim BK, Kim TS, Kim CJ, Shin MS (2011) The phosphodiesterase type-5 inhibitor, tadalafil, improves depressive symptoms, ameliorates memory impairment, as well as suppresses apoptosis and enhances cell proliferation in the hippocampus of maternal-separated rat pups. Neurosci Lett 488:26–30

    Article  CAS  PubMed  Google Scholar 

  33. Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD (2005) Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study. Circulation 111:742–746

    Article  CAS  PubMed  Google Scholar 

  34. Erol FS, Kaplan M, Tiftikci M, Yakar H, Ozercan I, Ilhan N, Topsakal C (2008) Comparison of the effects of octreotide and melatonin in preventing nerve injury in rats with experimental spinal cord injury. J Clin Neurosci 15:784–790

    Article  CAS  PubMed  Google Scholar 

  35. Taskiran D, Tanyalcin T, Sozmen EY, Peker GO, Gulmen V, Cagli S, Kanit L, Tekeli G, Barcin E, Zileli M, Kutay FZ (2000) The effects of melatonin on the antioxidant systems in experimental spinal injury. Int J Neurosci 104:63–73

    Article  CAS  PubMed  Google Scholar 

  36. de Vente J, Markerink-van Ittersum M, Vles JS (2006) The role of phosphodiesterase isoforms 2, 5, and 9 in the regulation of NO-dependent and NO-independent cGMP production in the rat cervical spinal cord. J Chem Neuroanat 31:275–303

    Article  PubMed  Google Scholar 

  37. Marsala J, Orendacova J, Lukacova N, Vanicky I (2007) Traumatic injury of the spinal cord and nitric oxide. Prog Brain Res 161:171–183

    Article  CAS  PubMed  Google Scholar 

  38. Rosen RC, Kostis JB (2003) Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 92:9M–18M

    Article  CAS  PubMed  Google Scholar 

  39. Muzaffar S, Shukla N, Angelini G, Jeremy JY (2004) Nitroaspirins and morpholinosydnonimine but not aspirin inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells. Circulation 110:1140–1147

    Article  CAS  PubMed  Google Scholar 

  40. Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G (2005) Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 47:214–220 (discussion 220–212)

    Google Scholar 

  41. Arikan DC, Bakan V, Kurutas EB, Sayar H, Coskun A (2010) Protective effect of tadalafil on ischemia/reperfusion injury of rat ovary. J Pediatr Surg 45:2203–2209

    Article  PubMed  Google Scholar 

  42. Sun L, Kuroiwa T, Ishibashi S, Katsumata N, Endo S, Mizusawa H (2006) Transition of areas of eosinophilic neurons and reactive astrocytes to delayed cortical infarcts after transient unilateral forebrain ischemia in Mongolian gerbils. Acta Neuropathol 111:21–28

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tayfur Ata Sökmen Medical Faculty, Mustafa Kemal University, 31700, Hatay, Turkey

    Murat Altaş, M. Aras, Y. Serarslan & N. Yılmaz

  2. Department of Anatomy, Tayfur Ata Sökmen Medical Faculty, Mustafa Kemal University, Hatay, Turkey

    S. Meydan

  3. Department of Histology and Embryology, School of Healthy Sciences, Mustafa Kemal University, Hatay, Turkey

    E. Nacar

  4. Department of Biochemistry, Tayfur Ata Sökmen Medical Faculty, Mustafa Kemal University, Hatay, Turkey

    K. T. Ulutaş

Authors
  1. Murat Altaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Aras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Meydan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Nacar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. T. Ulutaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Serarslan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N. Yılmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Murat Altaş.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Altaş, M., Aras, M., Meydan, S. et al. Effects of tadalafil on ischemia/reperfusion injury in rat brain. Acta Neurol Belg 114, 33–40 (2014). https://doi.org/10.1007/s13760-013-0234-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13760-013-0234-2

Keywords

Search

Navigation