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

J Dermatol Sci. 2018 May;90(2):144-153. doi: 10.1016/j.jdermsci.2018.01.006.

Abstract

Background: We previously identified that botulinum toxin A (BTX-A) suppressed pressure ulcer (PU) formation after cutaneous ischemia-reperfusion (I/R) injury; however, regulation of cutaneous I/R-induced oxidative and endoplasmic reticulum (ER) stress by BTX-B was not investigated. Additionally, the efficacy of BTX-B injection has never been examined.

Objective: Objective was to assess the effects of BTX-B on the formation of PU by cutaneous I/R injury, and the regulation of oxidative and ER stress in I/R injury by BTX-B.

Methods: BTX-B was subcutaneously injected into I/R area, and wound size, vascular damage, hypoxic area, and apoptotic cells in I/R area were analyzed. We evaluated the extent of oxidative and ER stress in I/R area by using OKD48 mice and ERAI mice, respectively, which enabled evaluating oxidative and ER stress through bioluminescence detection.

Results: BTX-B injection significantly suppressed the formation of PU by cutaneous I/R injury. Cutaneous I/R-induced vascular damage, hypoxic area, and number of oxidative-damaged cells and apoptotic cells were suppressed by BTX-B injection. BTX-B administration significantly inhibited I/R-induced oxidative stress signal in OKD48 mice. BTX-B reduced the I/R-induced oxidative stress-associated factors. BTX-B significantly inhibited the oxidant-induced reactive oxygen species and apoptosis of endothelial cells and fibroblasts. BTX-B significantly inhibited I/R-induced ER stress signal in ERAI mice. Cutaneous I/R injury-induced ER stress-response factors and GRP78/BiP and CHOP-positive cells in I/R area were significantly decreased by BTX-B injection.

Conclusion: BTX-B injection might have protective effects against PU formation after cutaneous I/R injury by reducing vascular damage, hypoxia-induced oxidative and ER stress, and apoptosis.

Keywords: Botulinum toxin; Cutaneous ischemia-reperfusion (I/R) injury; Endoplasmic reticulum (ER) stress; Oxidative stress; Pressure ulcers.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Botulinum Toxins, Type A / pharmacology
  • Botulinum Toxins, Type A / therapeutic use*
  • Disease Models, Animal
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects*
  • Fibroblasts
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Injections, Subcutaneous
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Oxidants / pharmacology
  • Oxidative Stress / drug effects*
  • Pressure Ulcer / drug therapy*
  • Pressure Ulcer / etiology
  • Pressure Ulcer / pathology
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / complications*
  • Reperfusion Injury / pathology
  • Skin / blood supply
  • Skin / drug effects
  • Skin / pathology
  • Treatment Outcome

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Hspa5 protein, mouse
  • Oxidants
  • Reactive Oxygen Species
  • rimabotulinumtoxinB
  • Botulinum Toxins, Type A