Methyl eugenol increases neural microcirculation to promote nerve repair by regulating endothelial cell and Schwann cell communication via Ptn/Sdc4

Abstract

Neuromicrocirculatory disorders often accompany nerve injury. Improving neural microcirculation can promote the repair of injured nerves. Methyl eugenol is a major bioactive component of Asarum heterotropoides and has been reported to exert analgesic effects in chronic pain. This study aimed to demonstrate that methyl eugenol can enhance neural microcirculation and thereby promote nerve repair. A combination of single-cell sequencing and mRNA sequencing revealed that pleiotrophin (Ptn)/syndecan-4 (Sdc4) is vital for coupling between endothelial cells and Schwann cells. A total of 32 rats were randomly assigned to four groups, namely, the Sham, chronic constriction injury (CCI) 7d, CCI 14d, and CCI 21d groups, to assess whether endothelial Schwann cell communication is diminished following CCI. After an endothelial cell-Schwann cell coculture system was established, methyl eugenol, Ptn siRNA, and Sdc4 siRNA were administered. In a separate experiment, 32 SD rats were randomly divided into four experimental groups: the Sham, CCI, ibuprofen, and methyl eugenol groups. CellChat analysis revealed that nerve injury reduced the degree of communication between endothelial cells and Schwann cells, especially communication via Ptn/Sdc4. CCI disrupted neural microcirculation, lowered Ptn levels, and increased Sdc4 expression. In cell experiments, methyl eugenol promoted rat aortic endothelial cells tube formation and increased the release of Ptn, which acted on Sdc4 in rat Schwann cells (RSC96) to promote migration, but did not directly promote RSC96 cell migration in the absence of endothelial cell-derived factors. Treatment with methyl eugenol increased neural microcirculation to promote nerve repair in rats subjected to CCI. In addition, methyl eugenol further increased Ptn levels. CCI led to neural microcirculatory dysfunction and nerve injury. Methyl eugenol promote nerve repair by enhancing neural microcirculation through regulation of endothelial cell and Schwann cell communication via Ptn/Sdc4.