Tetramethylpyrazine improved the survival of multiterritory perforator flaps by inducing angiogenesis and suppressing apoptosis via the Akt/Nrf2 pathway

Background: Multiterritory perforator flaps were commonly designed to cover the large soft-tissue defects in reconstructive surgery. But the high risk of partial necrosis in the distal portion of the flaps hindered their clinical application. The purpose of this study was to evaluate the effects of tetramethylpyrazine (TMP) on the survival of the multiterritory perforator flaps and to explore the underlying mechanism. Materials and methods: Seventy-two Sprague–Dawley rats underwent multiterritory perforator flap procedure and were divided into three groups with 24 each. Flap survival and water content were measured, and the area of angiogenesis and apoptosis in the ischemia skin flaps were assessed on the postoperative day 7. The expressions of angiogenesis-related protein VEGF and apoptosis-related protein Bax, Bcl-2 in each group were detected by Western blotting, which also had been used to assess the expressions levels of Akt, p-Akt, and Nrf2. Results: Following TMP treatment, the survival area and number of microvessels presented in the skin flaps increased and tissue edema reduced on postoperative day 7. The expressions of angiogenesis-related protein VEGF increased in the TMP treatment group than in the control group. In addition, compared with the control group, TMP inhibited apoptosis, and increased the expression levels of p-Akt, Nrf2 in the areas of ischemia. These effects were reversed by an Akt protein inhibitor LY294002. Similarly, treatment with LY294002 inhibited TMP induced by interfering the Akt/Nrf2 signaling pathway. Conclusion: These results illustrated that TMP could promote the survival of multiterritory perforator flaps by enhancing angiogenesis and attenuating apoptosis. These were involved in Akt/Nrf2 signaling pathway.