Statin Answers

Simvastatin pretreatment reduces the severity of limb ischemia in an experimental diabetes model

Cüneyt Köksoy MD, Erpulat Ozis MD, Atıl Çakmak MD, Uğur Yazgan PhD, Aylin Okcu-Heper MD, Aslıhan Köksoy MD, PhD, Ediz Demirpençe MD and U. Deniz Dinçer MD, PhD

Objective

The purpose of this study was to examine the effects of simvastatin pretreatment in the setting of acute limb ischemia–reperfusion injury in an experimental diabetes model that is associated with a high risk for limb loss.

Methods

Adult male Sprague-Dawley rats were randomized into two groups. Diabetes was induced in the first group by intravenous streptozotocin injection. The second group served as the nondiabetic group. Eight weeks after the streptozotocin injection, half of the rats in the diabetic and the nondiabetic groups were further randomized to receive either intraperitoneal simvastatin (1 mg/kg per day) or saline treatment for 6 weeks. Bilateral hind-limb ischemia was induced for 4 hours by the tourniquet method. After 24 hours of reperfusion, tissue samples were collected from the gastrocnemius and anterior tibial muscles bilaterally for measurement of muscle edema, percentage of necrosis, and malondialdehyde (MDA), glutathione, and myeloperoxidase (MPO) levels.

Results

Ischemic injury was more prominent in diabetic animals. The diabetic animals with limb ischemia exhibited a 7% increase in tissue edema, a 47% increase in muscle necrosis and MPO level, and a 15% reduction in glutathione levels compared with the nondiabetic animals (P < .05). Simvastatin treatment with 1 mg/kg for 6 weeks reduced the ischemic injury. Simvastatin pretreatment led to a 71% reduction in muscle necrosis in diabetic animals (P < .001). The protective effects of simvastatin pretreatment also correlated with a 23% improvement in tissue edema, a 75% reduction in tissue myeloperoxidase content, and a 71% increase in glutathione levels in diabetic animals (P < .01). Furthermore, skeletal muscle injury, characterized by tissue edema and leucosequestration, was significantly less severe with simvastatin pretreatment compared with the nondiabetic animals (P < .01).

Conclusion

Simvastatin pretreatment reduced limb ischemia–reperfusion injury in diabetic and nondiabetic animals. We conclude that simvastatin pretreatment may be a potential therapeutic intervention for skeletal muscle ischemia–reperfusion injury in the clinical setting.

Clinical Relevance

In this study, we obtained results suggesting that pretreatment with simvastatin for 6 weeks ameliorated the tourniquet-induced skeletal muscle ischemia–reperfusion injury in diabetic and nondiabetic rats. Our results hint that pretreatment with 3-hydroxy-3 methyl-glutaryl-coenzyme A reductase inhibitors (statins) may be useful in preventing and reducing the severity of acute ischemic events. These effects may be most prominent in patients suffering from circulation challenges such as those seen in diabetic patients. Nevertheless, this issue requires clinical evidence.