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The effect of KUS121, a novel VCP modulator, against ischemic injury in random pattern flaps
Koichi Yoshimoto1, Ryosuke Ikeguchi1, Takashi Noguchi1
1Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract:
Surgery using skin flaps is essential for soft tissue reconstruction. However, postoperative ischemic injury of the skin flap is a major complication and a top concern after the surgery. Currently, evidence-based drugs to fully prevent ischemic injury are not available. The purpose of this study was to evaluate the effect of KUS121, a VCP modulator, on flap ischemia using a rodent model. 26 Sprague-Dawley rats were randomly divided into two groups. The experimental group was intraperitoneally administered with 100 mg/kg KUS121 dissolved in 5% glucose solution 1 hour before surgery and once per day after surgery. The control group received the same amount of glucose solution on the same schedule. On day 7, 33.6 ± 3.7% of skin flaps in the control group had developed black necrosis compared with 26.4 ± 3.6% in the KUS121 group (p < 0.01). Immunohistochemistry showed that the KUS121 treatment reduced the number of apoptotic cells in the distal third of the flap (p < 0.01); moreover, in the KUS121-treated rats, the number of cells expressing CHOP, an endoplasmic reticulum (ER) stress marker, in the middle third of the flap was significantly lower than in the controls (p < 0.01). We examined the mRNA expression of Ddit3 (CHOP) and Casp3 (caspase-3) on day one after the surgery; mRNA expression of both genes appeared to decrease in the KUS121 group, as compared with the control group, although differences between groups were not significant. Thus, in a random pattern flap, KUS121 reduces ER stress and the number of apoptotic cells, thereby reducing ischemic damage of the flap.
Insights
KUS121, a VCP modulator, significantly reduced skin flap necrosis and apoptosis in a rodent model. This novel drug shows promise in preventing ischemic injury after reconstructive surgery.
Area of Science:
- Regenerative Medicine
- Surgical Innovation
- Molecular Biology
Background:
- Skin flap surgery is crucial for soft tissue reconstruction.
- Postoperative ischemic injury remains a significant complication, lacking effective preventative drugs.
- Understanding the molecular mechanisms of flap ischemia is vital for developing new treatments.
Purpose of the Study:
- To investigate the efficacy of KUS121, a VCP modulator, in mitigating skin flap ischemic injury.
- To evaluate the impact of KUS121 on apoptosis and endoplasmic reticulum (ER) stress markers in a rodent flap model.
- To assess KUS121's potential as a therapeutic agent for preventing flap necrosis.
Main Methods:
- A rodent model of random pattern skin flap was utilized with 26 Sprague-Dawley rats.
- Rats were randomly assigned to receive KUS121 (100 mg/kg) or a glucose placebo intraperitoneally before and after surgery.
- Flap necrosis, apoptosis, and ER stress markers (CHOP) were assessed using histology and immunohistochemistry.
Main Results:
- KUS121 treatment significantly reduced skin flap necrosis by day 7 (26.4% vs. 33.6% in controls, p < 0.01).
- Immunohistochemistry revealed reduced apoptotic cells and lower expression of the ER stress marker CHOP in KUS121-treated flaps (p < 0.01).
- While not statistically significant, mRNA expression of CHOP and caspase-3 tended to decrease in the KUS121 group.
Conclusions:
- KUS121 effectively reduces ischemic damage in random pattern skin flaps in rats.
- The drug mitigates flap ischemia by decreasing endoplasmic reticulum stress and apoptosis.
- KUS121 demonstrates potential as a novel therapeutic strategy to prevent skin flap necrosis.
