LB1612 Botulinum toxin B suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model: Possible regulation of oxidative and endoplasmic reticulum stress

Abstract

There is increasing evidence that cutaneous ischemia-reperfusion (I/R) injury is associated with the development of pressure ulcers (PUs). Botulinum toxin (BTX) suppress the release of neurotransmitters such as acetylcholine in the neuromuscular junction. Several studies have demonstrated that BTX enhanced the blood flow and survival of ischemic skin flaps in animal cutaneous flap models. The objective of this study is to assess the effects of BTX-B on the formation of PUs in the cutaneous I/R injury. In the cutaneous I/R injury mouse model, I/R injury-induced vascular damage, hypoxic area, and the number of oxidative stress-associated DNA-damaged cells and apoptotic cells were suppressed by BTX-B injection. BTX-B significantly inhibited cutaneous I/R injury-induced oxidative stress in OKD48 mice by bioluminescence. BTX-B reduced the I/R-induced mRNA levels of oxidative stress-associated factors, including HO-1, Nox2, and Nrf2. In an in vitro assay, BTX-B significantly inhibited the oxidant-induced ROS and apoptotic endothelial cells and fibroblasts. In addition, BTX-B significantly inhibited cutaneous I/R injury-induced endoplasmic reticulum (ER) stress in ERAI mice by bioluminescence. Cutaneous I/R injury-induced ER stress-response factors and GRP78/BiP- and CHOP-positive cells in the I/R area were significantly decreased by BTX-B injection. These results suggest that BTX-B injection might have protective effects against PU formation after cutaneous I/R injury by reducing vascular damage, inhibiting hypoxia-induced oxidative cellular damage, decreasing oxidative and ER stress, and preventing apoptosis.