Ivermectin Increases Random-Pattern Skin Flap Survival in Rats: The Novel Role of GABAergic System.

ABSTRACT

BACKGROUND: Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. METHODS: Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5 mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1ß and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. RESULTS: IVM 0.05 mg/kg could significantly increase flap survival compared with the control group (P < 0.001). Subeffective dose of baclofen (0.1 mg/kg) had synergistic effect with the subeffective dose of IVM (0.01 mg/kg) (P < 0.001), whereas bicuculline 1 mg/kg reversed the effect of IVM (0.05 mg/kg) (P < 0.001). IVM 0.05 mg/kg could also decrease the IL-1ß and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. CONCLUSIONS: IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."