β-N-oxalyl-L-α,β-diaminopropionic acid induces wound healing by stabilizing HIF-1α and modulating associated protein expression

Abstract

Background: β-N-oxalyl-L-α,β-diaminopropionic acid (L-ODAP) is a non-protein amino acid with haemostatic property present in Lathyrus sativus. It is considered to be the causative agent of neurolathyrism that occurs upon prolonged overconsumption of Lathyrus sativus seeds. L-ODAP is used as a haemostatic drug in surgical dressings. We previously reported that it can stabilize hypoxia inducible factor (HIF)-1α in normoxic conditions.

Hypothesis: We hypothesised that L-ODAP might affect wound healing by modulating cellular proliferation, migration and angiogenesis via HIF-1α stabilization.

Study design: We performed in vitro assays to evaluate wound healing activity of L-ODAP. Further, we prepared pharmaceutical gel containing L-ODAP and checked its effect on healing of full thickness excision wounds using Wistar albino rats.

Methods: Effect of L-ODAP on HT1080 cell line proliferation, migration and invasion was investigated. Further, gel containing L-ODAP was applied on full thickness excision wounds of Wistar rats. Western blot and zymography were performed with wound tissue extracts obtained 2 days post-wounding and histological and immunohistochemical analysis with regenerated tissue obtained 10 days post-wounding. Evaluation was made based on wound contraction percentage, histological analysis and protein expression levels.

Results: L-ODAP significantly (P < 0.05) affected wound healing both in vitro and in vivo. At non-toxic concentrations, it induced cell proliferation, migration, invasion and MMP-2 & -9 expressions. L-ODAP treated wounds healed faster than vehicle treated ones. Significantly higher expression level of HIF-1α, VEGF-A, PDGF-A and matrix metalloproteases were observed in L-ODAP treated wounds.

Conclusion: The present investigation explores potential of L-ODAP as a wound healing agent. L-ODAP positively affected wound healing both in vitro and in vivo and thus could be considered a natural wound healing agent.

Keywords: Hypoxia inducible factor-1α; L-ODAP; Lathyrus sativus; Wound healing.