Reduced neuropeptide signaling attenuates ischemia–reperfusion–induced pressure ulcer formation in SOD1-G93A mice

Amyotrophic lateral sclerosis (ALS) has been suggested to be associated with a reduced incidence of pressure ulcers, although the underlying mechanisms remain unclear. Here, we investigated pressure ulcer formation using a cutaneous ischemia–reperfusion (I/R) injury model in SOD1-G93A mice, a model of familial ALS. Under steady-state conditions, oxidative stress was markedly elevated in the dorsal root ganglia (DRG) and spinal cord compared with skin, accompanied by reduced PGP9.5 + nerve fiber density in the skin. Following I/R injury, SOD1-G93A mice exhibited significantly attenuated ulcer formation during the early phase after reperfusion compared with wild-type mice. Quantitative PCR analysis demonstrated the reduced expression of oxidative stress-related genes, proinflammatory cytokines, and neuropeptides and their receptors in I/R skin site. Histological analyses revealed reduced infiltration of M1 macrophages, decreased 8-OHdG-positive oxidative DNA damage, and fewer apoptotic cells. Consistently, a denervation model showed reduced wound size after cutaneous I/R injury. Despite elevated oxidative stress in DRG and spinal cord, cutaneous oxidative and inflammatory responses were suppressed in SOD1-G93A mice. These findings suggest that impaired peripheral innervation attenuates neuropeptide-mediated inflammatory pathways, thereby reducing tissue injury following I/R and leading to decreased pressure ulcer formation in ALS.