Critical limb ischemia (CLI) is a severe complication of
diabetes mellitus that occurs without effective
therapy. Excessive
reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications.
N-acetylcysteine (NAC) reduces
ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their
drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of
antioxidant enzymes including
superoxide dismutase (SOD)-1, SOD-3,
glutathione peroxidase (Gpx)-1,
catalase, and phosphorylated
insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo.
Body weight,
blood glucose, plasma
advanced glycation end-products (AGEs), plasma
insulin,
insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1,
catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in
blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and
insulin resistance.