Antifibrotic and anti-inflammatory properties of halofuginone in a rat craniectomy model

Abstract

BACKGROUND: Cranioplasty is the process of closing a defect after craniectomy using various materials. This procedure carries risks due to adhesions formed by fibrous scar tissue after craniectomy, which can lead to complications such as cerebrospinal fluid (CSF) fistula from dural damage and cerebral hematoma contusion from parenchymal damage, which can have serious consequences. Halofuginone, a low-molecular-weight molecule derived from Dichroa febrifuga, has demonstrated antifibrotic and anti-inflammatory properties by inhibiting type I collagen synthesis and the transforming growth factor-beta (TGF-β) signaling pathway. This study aimed to investigate the effects of halofuginone on fibrotic tissue formation following craniectomy in a rat model. METHODS: Twenty male Wistar rats underwent bilateral frontoparietal craniectomies and were divided into two groups: a control group treated with saline and a halofuginone group receiving oral halofuginone (1 mg/kg/day) for one week post-surgery. After 30 days, histopathological and ultrastructural analyses were performed to evaluate dura mater thickness, epidural fibrosis, arachnoid involvement, and bone regeneration. RESULTS: Halofuginone significantly reduced dura mater thickness (19.3±6.51 μm vs. 51.29±14.3 μm in controls, p<0.05) and epidural fibrosis grades, with fewer arachnoid adhesions observed in the halofuginone group (p<0.05). Electron microscopy revealed fewer active fibroblasts and thinner, disorganized collagen fibers in halofuginone-treated rats, suggesting inhibition of fibroblast activity and collagen production. No significant difference in bone regeneration was observed between the groups. CONCLUSION: These findings indicate that halofuginone effectively reduces fibrotic tissue formation at craniectomy sites, potentially by suppressing collagen synthesis and inflammatory responses. Further studies are warranted to explore its clinical applications in preventing postoperative fibrosis.