Prophylactic effects of edaravone on the extremity after limb replantation

doi:10.3969/j.issn.2095-4344.2014.24.008

Abstract

Abstract:

BACKGROUND: At present, there is no effective method to attenuate the severity of ischemia/reperfusion injury after limb replantation.
OBJECTIVE: To investigate the prophylactic effects of edaravone solution on extremity after limb replantation.
METHODS: According to different interventions, 18 healthy rabbits were randomly divided into three groups (n=6): edaravone group, control group and ischemia/reperfusion injury group. The replantation models in the left hindlimbs were established. In edaravone group, rabbits were perfused with edaravone solution (1.5 mg/kg) before the reperfusion. At 2, 4, 8, 12 hours, the tibialis anterior muscles tissues of rabbits were harvested, and the following levels were determined, including superoxide dismutase, myeloperoxidase, malondialdehyde, Ca²⁺-ATPase, Na⁺-K⁺-ATPase, wet weight/dry weight ratio. The morphology of tibialis anterior muscles was observed under light microscope.
RESULTS AND CONCLUSION: After ischemia and reperfusion, the skeletal muscle fibers appeared edema and apparent damage, a large number of inflammatory cells infiltrated. After the intervention of edaravone solution, the damage was attenuated, but aggravated along the time. Edaravone solution significantly increased the level of superoxide dismutase, myeloperoxidase, Ca²⁺-ATPase, Na⁺-K⁺-ATPase, and significantly decreased the level of malondialdehyde and wet weight/dry weight ratio (P < 0.05). Edaravone solution exerts apparent protective effects on extremity after limb replantation, and can improve the ischemia/reperfusion injury in the extremity (especially skeletal muscle) after limb replantation.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: organ transplantation, transplantation, tibia, reperfusion injury, extremities, myoblasts, skeletal, biological markers

CLC Number:

R318

Sun Hai-bo, Wei Jun-qiang, Chen Wei, Zhang Ying-ze, Zheng Zhan-le, Pan Jin-she. Prophylactic effects of edaravone on the extremity after limb replantation[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(24): 3814-3820.

Figures/Tables 4

2.3 生化指标检测结果 2.3.1 超氧化物歧化酶活性的变化超氧化物歧化酶是体内主要的氧自由基清除剂，通过不同时间点检测观察，各组均随着时间的增加，活性降低，差异均有显著性意义(P < 0.05，表1)。 2.3.2 丙二醛含量的变化该指标为骨骼肌发生过氧化反应后的主要底物，缺血再灌注后丙二醛含量显著增加，且随时间的增加而增加，经过依达拉奉治疗后含量降低，但仍高于对照组(P < 0.05)，该指标与缺血再灌注损伤的程度呈正相关(表2)。 2.3.3 过氧化物酶含量的变化中性粒细胞嗜天青颗粒中含量较高且恒定的酶，可反映中性粒细胞在组织内聚集的程度，缺血再灌注兔体内骨骼肌过氧化物酶含量显著增加(P < 0.05)，而经过依达拉奉保护后，个时间点指标均降低，随着时间的增加而逐渐增加，该指标与缺血再灌注损伤的程度呈正相关(表3)。 2.3.4 Na+-K+-ATP酶含量的变化是细胞膜上的固有蛋白，其活性的下降是膜结构损伤的敏感性指标，兔缺血再灌注损伤时，Na+-K+-ATP酶含量各时间均降低，却随着时间的增加而逐渐降低，经过依达拉奉保护后，各时间点各均有所增加，但仍显著低于对照组(P < 0.0)，该指标与缺血再灌注损伤的程度呈负相关(表4)。 2.3.5 Ca2+-ATP酶含量的变化是细胞膜上的固有蛋白，其活性的下降是膜结构损伤的敏感性指标，兔缺血再灌注损伤时，过氧化物酶含量显著降低(P < 0.05)，且随着时间的增加下降更多，给予依达拉奉治疗后各指标上调，但仍低于对照组(P < 0.05)，该指标与缺血再灌注损伤的程度呈负相关(表5)。 2.3.6 湿质量/干质量比值的变化该指标反映组织水肿程度，兔缺血再灌注后水肿程度明显加剧，随时间增加而加重(P < 0.05)，但给予依达拉奉保护后不同时间湿质量/干质量比值指标均下降，但仍高于对照组(P < 0.05)，与缺血再灌注损伤的程度呈正相关(表6)。"

References

[1] 张震宇,杨卫良,王立峰,等.断肢再植肌组织缺血再灌注损伤的细胞凋亡及Bax、Bcl－2的表达[J].哈尔滨医科大学学报,2006,40 (5):371-374.
[2] 王悦书,王国君,张弘,等.缺血兔骨骼肌变性的组织学研究[J].吉林大学学报(医学版),2002,28(4):366-368.
[3] 张志新,王国君,路来金,等.生物发光法短时内判断温缺血断肢再植时限的实验研究[J].白求恩医科大学学报,2000,26(5): 496-498.
[4] Yoshida H, Metoki N, Ishikawa A, et al. Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res. 2010; 66(3):284-289.
[5] Fu JQ, Wang DF, Liu H, et al. A comparative study on the protection effect of nerve growth factor and edaravone pretreatment against cerebralischemia/reperfusion injury. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010;22(4): 226-229.
[6] Srinivasan K, Sharma SS. Edaravone Offers Neuroprotection in a Diabetic Stroke Model via Inhibition of Endoplasmic Reticulum Stress. Basic Clin Pharmacol Toxicol. 2011;58(6): 1742-1749.
[7] Connell BJ, Saleh MC, Kucukkaya I, et al. UPEI-300, a conjugate of lipoic acid and edaravone, mediates neuroprotection in ischemia/reperfusion. Neurosci Lett. 2014 Jan 3. pii: S0304-3940(13)01141-5.
[8] Yao N, Wang DF, Song X, et al. Neuroprotective effects of combined pretreatment with edaravone and propofol on neonatal rat cerebral cortical neurons with ischemia/ reperfusion injury in vitro. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012;24(5):286-289.
[9] Jiao L, Zhang J, Li Z, et al. Edaravone alleviates delayed neuronal death and long-dated cognitive dysfunction of hippocampus after transient focal ischemia in Wistar rat brains. Neuroscience. 2011;19;182:177-183.
[10] Herlambang B, Orihashi K, Mizukami T, et al. New method for absolute spinal cord ischemia protection in rabbits. J Vasc Surg. 2011;54(4):1109-1116.
[11] Ergenoglu M, Erba? O, Akdemir A, et al. Attenuation of ischemia/reperfusion-induced ovarian damage in rats: does edaravone offer protection? Eur Surg Res. 2013;51(1-2): 21-32.
[12] Kara M, Daglioglu YK, Kuyucu Y, et al. The effect of edaravone on ischemia-reperfusion injury in rat ovary. Eur J Obstet Gynecol Reprod Biol. 2012;162(2):197-202.
[13] Shimoda M, Iwasaki Y, Okada T, et al. Edaravone inhibits apoptosis caused by ischemia/reperfusion injury in a porcine hepatectomy model. World J Gastroenterol. 2012;18(27): 3520-3526.
[14] Yamamura M, Miyamoto Y, Mitsuno M, et al. Edaravone protects against tissue damage in the lung and kidney induced by myonephropathic metabolic syndrome. Int J Angiol. 2010;19(1):e38-40.
[15] Kikuchi K, Tancharoen S, Takeshige N, et al. The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci. 2013;14(7): 13909-13930.
[16] Zhang W, Guo Y, Yu S, et al. Effects of edaravone on the expression of β-defensin-2 mRNA in lung tissue of rats with myocardial ischemiareperfusion. Mol Med Rep. 2013;7(5): 1683-1687.
[17] Zhang GM, Wang Y, Li XY, et al. Pharmacological postconditioning with lactic acid and low dose edaravone could attenuate myocardialreperfusion injury through mitochondrial pathway. Zhonghua Xin Xue Guan Bing Za Zhi. 2013;41(8):647-653.
[18] Yamamura M, Miyamoto Y, Mitsuno M, et al. Edaravone reduces mitochondrial damage due to reperfusion injury following leg ischemia in rats. Int J Angiol. 2010;19(4):e129-131.
[19] Yamamura M, Miyamoto Y, Mitsuno M, et al. Edaravone Suppresses Reperfusion Injury following Leg Ischemia in Rats: A Transmission Electron Microscopic Study. Int J Angiol. 2013;22(4):267-270.
[20] 段永壮,王增涛,钟世镇,等.依达拉奉对深低温保存大鼠断肢再植后缺血再灌注损伤的影响.中国组织工程与临床康复, 2007, 11(8):1416-1419.
[21] Hori K, Tsujii M, Iino T, et al. Protective effect of edaravone for tourniquet-induced ischemia-reperfusion injury on skeletal muscle in murine hindlimb. BMC Musculoskelet Disord. 2013; 14:113
[22] Liu S, Li R, Ni X, et al. Perfluorocarbon-facilitated CNS oxygen toxicity in rats: reversal by edaravone. Brain Res. 2012;1471:56-65.
[23] Gao Y, Ding XS, Xu S, et al. Neuroprotective effects of edaravone on early brain injury in rats after subarachnoid hemorrhage.Chin Med J. 2009;122(16):1935-1940.
[24] Zhang P, Li W, Li L, Wang N, et al. Treatment with edaravone attenuates ischemic brain injury and inhibits neurogenesis in the subventricular zone of adult rats after focal cerebral ischemia and reperfusion injury. Neuroscience. 2012;201: 297-306.
[25] Zhang N, Miki KK, Ryota T, et al.Edaravone reduces early accumulation of oxidative products and sequential inflammatory reponses after transient focal ischemia in mice brain.Stroke. 2005;36(3):2220-2225.
[26] Irie H, Kato T, Ikebe K, et al. Antioxidant effect of MCI-186,a new free radical scavenger,on ischemia-reperfusion injury in a rat hindlimb amputation model.J Surg Res. 2004;120(2): 312-319.
[27] Blaisdell FW.The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome:a review. Cardiovasc Surg. 2002;10(6):620-630.
[28] Sheu EG, Oakes SM, Ahmadi-Yazdi C,et al. Restoration of skeletal muscle ischemia-reperfusion injury in humanized immunodeficient mice. Surgery. 2009;146(2):340-346.
[29] ]Serviddio G,di Venosa N,Fedeeici A,et al. Brief hypoxia before normoxic reperfusion (postconditioning) protects the heart against ischemia-reperfusion injury by preventing micochonndria peroxyde production and glutahione depletion. FASEB J.2005;19(3)345-361.
[30] Bolte CS,Liao S,Gross GJ,et al.Rrmote preconditioning- endocrine factors in organ protection against ischemic injury.Endocr Metab Immune Disord Drug Targets. 2007;7(3): 167-175.