Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811.

PloS one

PubMedID: 24968303

Garbaisz D, Turoczi Z, Aranyi P, Fulop A, Rosero O, Hermesz E, Ferencz A, Lotz G, Harsanyi L, Szijarto A. Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811. PLoS ONE. 2014;9(6):e101067.
INTRODUCTION
Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP).

OBJECTIVES
Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.

MATERIALS AND METHODS
Wistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-a and IL-6 levels were measured.

RESULTS
Less significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p?=?0.017). Muscle mitochondrial viability proved to be significantly higher (p?=?0.001) and renal function parameters were significantly better (creatinine: p?=?0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-a and IL-6 levels were significantly lower (TNF-a: p?=?0.003, IL-6: p?=?0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p?=?0.014; p<0.001) in the NIM-IR group than in the IR group.

CONCLUSION
NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.