Effect of Systemic Piracetam Treatment on Flap Survival and Vascular Endothelial Growth Factor Expression after Ischemia-Reperfusion Injury

ABSTRACT

The effects of piracetam on flap survival, ischemia-reperfusion (I/R) injury, and vascular endothelial growth factor (VEGF) expression were evaluated in this study. Unipedicled epigastric flap model was used in 36 rats and was evaluated within 4 groups. The flap was elevated and untreated in Group 1. Postoperative piracetam treatment was given for 7 days in Group 2. In Group 3, 4 hours of ischemia and 2 hours of reperfusion were applied. I/R was applied to Group 4 and piracetam was given 30 minutes before reperfusion and postoperatively for 7 days. Laser Doppler flowmetry was used to measure blood flow changes. VEGF expression was determined using immunohistochemical methods on tissue samples taken after the completion of 2 hours reperfusion in groups 3 and 4. Flap necrosis was measured on the day 7 in all groups. Blood flow rates did not show significant difference between piracetam treated and untreated I/R groups. Piracetam significantly reduced necrosis area both in ischemic and nonischemic flaps (p < 0.05). VEGF expression was significantly increased in piracetam-treated Group 4 compared with Group 3 (p = 0.005). This experimental study demonstrates that systemic piracetam treatment improves survival of pedicled flaps, reduces necrosis amounts, and increases VEGF expression in I/R induced flaps.

Piracetam - Nootropil - ischemia-reperfusion injury - vascular endothelial growth factor expression - flap survival

REFERENCES

• 1 Jones N F. Intraoperative and postoperative monitoring of microsurgical free tissue transfers.  Clin Plast Surg. 1992;  19 (4) 783-797
• 2 Morris S F, Pang C Y, Zhong A, Boyd B, Forrest C R. Assessment of ischemia-induced reperfusion injury in the pig latissimus dorsi myocutaneous flap model.  Plast Reconstr Surg. 1993;  92 (6) 1162-1172
• 3 Carden D L, Granger D N. Pathophysiology of ischaemia-reperfusion injury.  J Pathol. 2000;  190 (3) 255-266
• 4 Anaya-Prado R, Toledo-Pereyra L H, Lentsch A B, Ward P A. Ischemia/reperfusion injury.  J Surg Res. 2002;  105 (2) 248-258
• 5 Angel M F, Ramasastry S S, Swartz W M et al.. The critical relationship between free radicals and degrees of ischemia: evidence for tissue intolerance of marginal perfusion.  Plast Reconstr Surg. 1988;  81 (2) 233-239
• 6 Askar I, Bozkurt M. Protective effects of immunosuppressants and steroids against ischemia-reperfusion injury in cremaster muscle flap at microcirculatory level.  Microsurgery. 2002;  22 (8) 361-366
• 7 Cordeiro P G, Mastorakos D P, Hu Q Y, Kirschner R E. The protective effect of L-arginine on ischemia-reperfusion injury in rat skin flaps.  Plast Reconstr Surg. 1997;  100 (5) 1227-1233
• 8 Im M J, Manson P N, Bulkley G B, Hoopes J E. Effects of superoxide dismutase and allopurinol on the survival of acute island skin flaps.  Ann Surg. 1985;  201 (3) 357-359
• 9 Khiabani K T, Kerrigan C L. The effects of the nitric oxide donor SIN-1 on ischemia-reperfused cutaneous and myocutaneous flaps.  Plast Reconstr Surg. 2002;  110 (1) 169-176
• 10 Sagi A, Ferder M, Levens D, Strauch B. Improved survival of island flaps after prolonged ischemia by perfusion with superoxide dismutase.  Plast Reconstr Surg. 1986;  77 (4) 639-644
• 11 Suzuki S, Yoshioka N, Isshiki N, Hamanaka H, Miyachi Y. Involvement of reactive oxygen species in post-ischaemic flap necrosis and its prevention by antioxidants.  Br J Plast Surg. 1991;  44 (2) 130-134
• 12 Kryger Z, Dogan T, Zhang F et al.. Effects of VEGF administration following ischemia on survival of the gracilis muscle flap in the rat.  Ann Plast Surg. 1999;  43 (2) 172-178
• 13 Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia.  Seizure. 2001;  10 (4) 287-293
• 14 Kessler J, Thiel A, Karbe H, Heiss W D. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients.  Stroke. 2000;  31 (9) 2112-2116
• 15 Mondadori C, Bhatnagar A, Borkowski J, Häusler A. Involvement of a steroidal component in the mechanism of action of piracetam-like nootropics.  Brain Res. 1990;  506 (1) 101-108
• 16 Ricci S, Celani M G, Cantisani T A, Righetti E. Piracetam in acute stroke: a systematic review.  J Neurol. 2000;  247 (4) 263-266
• 17 Rossillon D, Vanwyck R, Bayet B, Calteux N, De Coninck A. The action of piracetam in ischaemic flaps.  Br J Plast Surg. 1987;  40 (5) 459-466
• 18 Payette J R, Kohlenberg E, Leonardi L et al.. Assessment of skin flaps using optically based methods for measuring blood flow and oxygenation.  Plast Reconstr Surg. 2005;  115 (2) 539-546
• 19 Lepore D A, Knight K R, Bhattacharya S et al.. Drug mixture which improves survival of ischemic rabbit epigastric skin flaps.  Microsurgery. 1994;  15 (10) 685-692
• 20 Basile A P, Fiala T G, Yaremchuk M J, May Jr J W. The antithrombotic effects of ticlopidine and aspirin in a microvascular thrombogenic model.  Plast Reconstr Surg. 1995;  95 (7) 1258-1264
• 21 Lee C, Kerrigan C L. Ibuprofen treatment of ischemic musculocutaneous flaps.  Ann Plast Surg. 1994;  32 (3) 300-304
• 22 Peter F W, Franken RJPM, Wang W Z et al.. Effect of low dose aspirin on thrombus formation at arterial and venous microanastomoses and on the tissue microcirculation.  Plast Reconstr Surg. 1997;  99 (4) 1112-1121
• 23 Mowlavi A, Ghavami A, Song Y H, Neumeister M. Limited use of cyclosporin A in skeletal muscle ischemia—reperfusion injury.  Ann Plast Surg. 2001;  46 (4) 426-430
• 24 Unal S, Ozmen S, DemIr Y et al.. The effect of gradually increased blood flow on ischemia-reperfusion injury.  Ann Plast Surg. 2001;  47 (4) 412-416
• 25 Mindus P, Cronholm B, Levander S E, Schalling D. Piracetam-induced improvement of mental performance. A controlled study on normally aging individuals.  Acta Psychiatr Scand. 1976;  54 (2) 150-160
• 26 Bick R L. In-vivo platelet inhibition by piracetam.  Lancet. 1979;  2 (8145) 752-753
• 27 Nalbandian R M, Murayama M, Henry R L. Restoration of phagocytosis and oxidative metabolism by Piracetam in failing human neutrophils: a qualitative assessment.  Clin Immunol Immunopathol. 1983;  28 (2) 155-169
• 28 Gianello P, Janssen T, Chatzopoulos C et al.. Beneficial effect of piracetam on renal blood flow in ischemically injured kidneys in the rat.  Transplant Proc. 1988;  20 (5) 914-916
• 29 Horvath B, Marton Z, Halmosi R et al.. In vitro antioxidant properties of pentoxifylline, piracetam, and vinpocetine.  Clin Neuropharmacol. 2002;  25 (1) 37-42
• 30 Croisile B, Trillet M, Fondarai J, Laurent B, Mauguière F, Billardon M. Long-term and high-dose piracetam treatment of Alzheimer's disease.  Neurology. 1993;  43 (2) 301-305
• 31 Rameis H, Hitzenberger G, Kutscher R, Manigley C. Pharmacokinetics of piracetam: a study on the bioavailability with special regard to renal and non-renal elimination.  Int J Clin Pharmacol Ther. 1994;  32 (9) 458-465
• 32 Nalbandian R M, Henry R L, Burek C L et al.. Diminished adherence of sickle erythrocytes to cultured vascular endothelium by piracetam.  Am J Hematol. 1983;  15 (2) 147-151
• 33 Banbury J, Siemionow M, Porvasnik S, Petras S, Browne E. Improved perfusion after subcritical ischemia in muscle flaps treated with vascular endothelial growth factor.  Plast Reconstr Surg. 2000;  106 (7) 1541-1546
• 34 Pang Y, Lineaweaver W C, Lei M P et al.. Evaluation of the mechanism of vascular endothelial growth factor improvement of ischemic flap survival in rats.  Plast Reconstr Surg. 2003;  112 (2) 556-564
• 35 Machens H G, Salehi J, Weich H et al.. Angiogenic effects of injected VEGF165 and sVEGFR-1 (sFLT-1) in a rat flap model.  J Surg Res. 2003;  111 (1) 136-142
• 36 Zhang F, Oswald T, Lin S et al.. Vascular endothelial growth factor (VEGF) expression and the effect of exogenous VEGF on survival of a random flap in the rat.  Br J Plast Surg. 2003;  56 (7) 653-659
• 37 Erdmann D, Sweis R, Wong M S, Niklason L E, Laney T V, Levin L S, Klitzman B, Olbrich K C. Vascular endothelial growth factor expression in pig latissimus dorsi myocutaneous flaps after ischemia reperfusion injury.  Plast Reconstr Surg. 2003;  111 775-780