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


CONCLUSIONS
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.
Köksoy
Cüneyt
C
Department of General Surgery, Ankara University, Ankara, Turkey. cuneytkoksoy@hotmail.com
Oziş
Erpulat
E
Cakmak
Atil
A
Yazgan
Uğur
U
Okcu-Heper
Aylin
A
Köksoy
Aslihan
A
Demirpençe
Ediz
E
Deniz Dinçer
U
U
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004487:Edema / Q000517:prevention & control; D005978:Glutathione / Q000378:metabolism; D006614:Hindlimb; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007511:Ischemia / Q000150:complications; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000517:prevention & control; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D012720:Severity of Illness Index; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014111:Tourniquets
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008315:Malondialdehyde; D019821:Simvastatin; D009195:Peroxidase; D005978:Glutathione