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

Abstract

IntroductionOperation 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).ObjectivesOur aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.Materials and methodsWistar 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-α and IL-6 levels were measured.ResultsLess 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-α and IL-6 levels were significantly lower (TNF-α: 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.ConclusionNIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.

Skeletal muscle ischemia–reperfusion injury and cyclosporine A in the aging rat

“…In young rats, we previously observed that CsA restored skeletal muscle mitochondrial coupling and reduced ROS production during hindlimb IR [23]. Similarly, CsA enhanced mitochondrial recovery after lattissimus dorsi flaps IR in pigs [22] and a nonimmunosuppressive CsA derivative (NIM-811) reduced skeletal muscle injury after IR [24]. Remarkably, the protective effects provided by 10 mg/kg intravenous CsA, given 5 min before reperfusion (reduced muscle infarction, reduced myeloperoxidase activity, and reduced muscle calcium content), were abolished when a mPTP opener atractyloside was injected [22] supporting that CsA is still able to maintain the mPTP in the 'closed' mode, even when provided after ischemia.…”

“…CsA inhibits mitochondrial transition pore (mPTP) opening and therefore antagonizes apoptosis. CsA given at the onset of reperfusion was shown to protect myocardial [21] and skeletal muscles [22][23][24] from IR-induced injury in adult patients and rats, respectively.…”

The influence of allopurinol and post-conditioning on lung injuries induced by lower-limb ischemia and reperfusion in Wistar rats

“…There is an increase in local injury, necrosis and rhabdomyolysis, as well as of their systemic repercussions. The metabolics and pro-inflammatory cytokines originating from muscular injury may induce Systemic Inflammatory Response Syndrome, and may affect distant organs, such as kidneys, lung and gastrointestinal tract -multiple organ dysfunction 13 . Among these organs, the lung was the one analyzed in the present study.…”

The reno-protective effects of atorvastatin in crush syndrome and rhabdomyolysis:is there a dilemma?

“…They reported that muscle mitochondrial viability proved to be significantly higher and renal function parameters significantly better in the treatment group (18).…”