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Original Experimental Research
Journal of Chinese Integrative Medicine: Volume 3   January, 2005   Number 1

DOI: 10.3736/jcim20050110
Effects of Shenmai Huoxue Decoction on early diabetic peripheral neuropathy in rats
1. XUE Hong-Li (Institute of Chinese Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China E-mail: wj6518@fudan.edu.cn)
2. WANG Wen-Jian (Institute of Chinese Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China E-mail: wj6518@fudan.edu.cn)
3. CHEN Jian-Qiu (Institute of Chinese Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China )

Objective: To evaluate the effects of Shenmai Huoxue Decoction (SMHXD) on early diabetic peripheral neuropathy (DPN) in rats.

Methods: The rats were randomly divided into 3 groups: normal group, diabetic model group and SMHXD-treated diabetic group. The diabetic rats were induced by streptozotocin (STZ) intraperitoneally. After the treatment, sensory nerve conduction velocity (SNCV) of caudal nerve was detected with evoked electromyography, and the activity of aldose reductase (AR) in erythrocytes and the concentration of endothelin (ET) in plasma were measured.

Results: It was showed that the SNCV reduced significantly and the activity of AR in erythrocytes and the concentration of ET in plasma were increased significantly in diabetic group as compared with those in the normal group. The SNCV was increased, and the activity of AR in erythrocytes and the concentration of ET in plasma were improved significantly in SMHXD-treated diabetic group after the treatment.

Conclusion: The results indicate that SMHXD can alleviate the lesion of DPN in the early stage of diabetic rats.

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J Chin Integr Med, 2005, 3(1): 31-34

Correspondence to: Prof. WANG Wen-Jian. E-mail: wj6518@fudan.edu.cn  

基金项目: 国家教委高校博士点科研基金资助项目(No.200043)

作者简介: 薛红丽(1972-),女,在读博士研究生. E-mail: xuehongli@sohu.com

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     糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)是糖尿病最常见的并发症之一,目前对DPN的治疗效果尚不尽如人意。我们根据DPN患者的临床表现特点,从气虚血瘀论治,用参麦活血饮(由红参、红花、麦冬组成)治疗DPN取得了一定临床疗效[1],为探讨其作用机制,我们观察了该方对糖尿病大鼠感觉神经传导速度(sensory nerve conduction velocity,SNCV)及红细胞醛糖还原酶(aldose reductase,AR)活性和血浆内皮素(endothelin,ET)水平的影响。

 
   

1 材料与方法
1.1 动物模型建立及分组
 实验选用SD雄性大鼠,体质量(200±20)g,禁食12 h后,按60 mg/kg的剂量一次性腹腔注射链脲佐菌素(streptozotocin,STZ)(Sigma公司产品,用pH 4.5的0.1 mol/L柠檬酸钠缓冲液稀释),72 h后由尾静脉采血测定血糖,凡血糖高于16.7 mmol/L者,被纳入实验。将入选的模型动物随机分为两组,糖尿病模型组(11只)和参麦活血饮治疗组(12只)。并以体质量、年龄相匹配的正常大鼠11只作为正常对照组,该组大鼠腹腔注射相应容积的柠檬酸缓冲液。
1.2 药物治疗 造模1周后,参麦活血饮治疗组予灌胃参麦活血饮(Shenmai Huoxue Decoction, SMHXD), 5 g·kg-1·d-1;正常对照组和糖尿病模型组用相应容积的饮用水灌胃, 1次/d,连续4周。每2周测定体质量和血糖各1次。用药4周后测定大鼠体质量、血糖、SNCV、红细胞AR活性及血浆ET水平。
1.3 神经电生理检测 大鼠腹腔注射10%水合氯醛(350 mg/kg),麻醉后俯卧固定,采用意大利Phasis四通道肌电诱发电位仪测定SNCV。刺激点位于尾部远端,记录电极位于尾部近端,记录电极距离刺激点约2~3 cm[2]。刺激量从较小开始,逐渐增加到超强刺激。SNCV为复合动作电位传导的距离与复合动作电位出现的潜伏期比值(m/s)。测定时保持被检测肢体温度在37℃左右。
1.4 红细胞AR活性的测定
1.4.1 主要试剂与仪器 还原型辅酶Ⅱ,美国Sigma公司产品;DL-甘油醛,意大利Roth公司产品;其他均为国产分析纯试剂。Hitachi 650-60型荧光分光光度计。
1.4.2 测定方法 采用荧光法,参照沈守祥等[3]和周云平等[4]报道的方法进行测定。 取血1 ml加入预冷的肝素抗凝管中, 3 000 r/min离心5 min,分离血浆。红细胞层以10倍体积冷等渗盐水冲洗3次,按红细胞∶蒸馏水=1∶1.5的体积比制成溶血液,4℃,10 000 r/min离心30 min,取上清测AR。血红蛋白定量采用氰化高铁血红蛋白法。
1.5 血浆ET水平的测定 选用放射免疫法测定,试剂盒由北京东亚免疫技术研究所提供,具体操作按试剂盒说明进行。
1.6 统计学方法 各项数据以`x±s表示,各组间样本均数比较采用单因素方差分析。

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2 结 果
2.1 参麦活血饮对糖尿病大鼠体重、血糖的影响
 治疗4周后,与正常对照组相比,糖尿病模型组和参麦活血饮治疗组体重明显减轻,血糖明显升高(P<0.05)。糖尿病模型组与参麦活血饮治疗组相比差异无统计学意义(P>0.05)。见表1。

表1 参麦活血饮对糖尿病大鼠体重、血糖的影响
Tab 1 Effects of SMHXD on weight and blood glucose concentration of experimental rats
                                                                             ( `x±s) 

  Group

n

Weight
(g)

Blood glucose
(mmol/L)

Normal group

11

323.82±29.30

4.01±0.56

Diabetic group

11

268.82±20.56*

31.13±3.05*

SMHXD-treated group

12

261.67±17.38*

26.97±5.44*

*P<0.05, vs normal group

2.2 参麦活血饮对糖尿病大鼠SNCV的影响 治疗4周后,与正常对照组相比,糖尿病模型组感觉神经传导速度明显减慢,潜伏期延长,波幅减小(P<0.05)。参麦活血饮能使上述改变减轻,与糖尿病模型组相比其差异有统计学意义(P<0.05)。见表2。

表2 参麦活血饮对糖尿病大鼠感觉神经传导速度的影响
Tab 2 Effects of SMHXD on nerve conduction velocity of experimental rats
                                                                                          ( `x±s)

  Group

n

SNCV (m/s)

Latency (ms)

Amplitude (mV)

Normal group

11

34.85±3.00

0.89±0.12△

41.05±10.83

Diabetic group

10

23.46±5.45

1.28±0.23

12.39±5.80

SMHXD-treated group

12

29.47±3.68

1.00±0.15△

36.19±7.05

P<0.05, vs diabetic group

2.3 参麦活血饮对糖尿病大鼠红细胞AR活性及血浆ET水平的影响 治疗4周后,与正常对照组相比,糖尿病模型组红细胞AR活性、血浆ET水平均明显升高(P<0.05)。参麦活血饮治疗组上述改变减轻,与糖尿病模型组相比,红细胞AR活性、血浆ET水平均明显降低(P<0.05)。参麦活血饮治疗组与正常对照组相比,各数据间差异无统计学意义(P>0.05)。见表3。

表3 参麦活血饮对糖尿病大鼠红细胞AR活性及血浆ET水平的影响
Tab 3 Effects of SMHXD on activity of AR in erythrocytes and concentration of ET in plasma in experimental rats
                                                                                           ( `x±s)

  Group

AR (U/g Hb)

ET (ng/L)

 Normal group

0.76±0.14n=9)

233.20±25.46n=10)

 Diabetic group

1.42±0.44 (n=10)

304.54±47.15 (n=10)

 SMHXD treated group

0.78±0.15n=6)

237.01±48.23n=11)

P<0.05, vs diabetic group

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3 讨 论
     高血糖时多元醇代谢通路增强是DPN的重要发病机制之一,AR是多元醇通路的重要限速酶。高血糖状态时,AR活性增强,该通路被激活,代谢加速,使细胞内山梨醇和果糖含量增高,肌醇减少,最终导致细胞Na+-K+-ATP酶活性降低,从而破坏细胞膜结构与功能的完整性。STZ诱导的糖尿病大鼠神经组织中山梨醇和果糖含量增高,肌醇含量减少,Na+-K+-ATP酶活性降低,运动和感觉神经传导速度明显减慢。动物及临床实验表明醛糖还原酶抑制剂(aldose reductase inhibitor,ARI)可以降低神经细胞内的山梨醇水平,提高细胞内肌醇含量及Na+-K+-ATP酶活性,明显改善神经传导速度及神经的形态学异常 [5,6]
     大量的研究证实在DPN的发生机制中,除了持续高血糖引起的代谢紊乱外,血管损害引起的神经内膜缺血可能是糖尿病早期神经传导损害的一个重要因素。神经内膜缺血与神经结构和功能的改变密切相关,STZ诱导的糖尿病大鼠毛细血管基底膜明显增厚,有髓纤维的大小和密度显著降低,运动神经传导速度明显降低。DPN患者长期高血糖,血管内皮缺血、缺氧导致血管基底膜增厚,内皮细胞肿胀、增生等病理改变,同时血液黏、浓、聚性增加,呈高凝状态,血液流动性下降,神经微血管的血流减慢,而致神经内膜缺氧,神经结构和功能发生改变[7,8]
     ET是由内皮细胞产生的具有强烈缩血管作用的生物活性多肽,其对多种细胞有促分泌、增殖效应,参与了多种生理过程的调节,是一种多功能的细胞因子。但其过量释放可通过影响血流动力学的改变而参与微血管病变的发病。高血糖可引起ET RNA的高度表达,ET水平升高。高水平的ET与神经血流减少及神经组织的病理改变有关,引起神经缺血导致神经传导的部分阻滞[9~11]。本实验结果与以上报道基本一致,运用参麦活血饮治疗后,糖尿病大鼠血浆ET水平下降,提示该疗法可能是通过改善血管内皮功能,恢复神经血供和营养而起作用的。
     传统中医认为糖尿病的基本病机是阴虚燥热。燥热之邪初则耗阴,久则伤气,迁延日久,可阴损及阳;气主运化,可化生水谷精微,维持物质的正常代谢,气虚则导致包括糖代谢在内的各种代谢的紊乱;血的运行和津液的输布都有赖气的激发和推动,气虚推动乏力,阴虚无水行舟皆可导致血流迟缓,瘀血内生,最终出现气虚血瘀。DPN患者临床可见神疲乏力、心悸气短等气虚之象,同时可见肢体疼痛或麻木、手足青紫,舌质紫暗或舌体瘀斑、瘀点,脉细涩等瘀血表现,可以认为气虚血瘀是DPN的病机。我们以益气为本,选用大补元气之红参,助运化,输精微,使气旺津生,纠正机体代谢紊乱;同时选用血中之气药红花活血化瘀,既可改善微循环,又可纠正代谢紊乱,主要用于DPN早期病变。
     本实验结果证实,参麦活血饮能明显延缓糖尿病大鼠SNCV的减慢,经参麦活血饮治疗后糖尿病大鼠红细胞AR活性和血浆ET水平降低,提示参麦活血饮具有抑制多元醇代谢通路和改善神经血供的作用,这可能是参麦活血饮改善糖尿病大鼠周围神经功能的机制所在。但参麦活血饮并不能有效降低糖尿病大鼠的血糖,说明降血糖并不是其主要的作用机制,其作用的具体机制,还需进一步探讨。

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References
1. 陈剑秋, 石志芸, 王文健, 等. 益气养阴活血方治疗糖尿病周围神经病的临床观察[J]. 上海中医药杂志, 2002, 36(7) : 23-24.
  
2. Kato N, Makino M, Mizuno K, et al. Serial changes of sensory nerve conduction velocity and minimal F-wave latency in streptozotocin-induced diabetic rats[J]. Neurosci Lett, 1998, 244(3) : 169-172.
    
3. 沈守祥, 董砚虎, 逢力男, 等. 红细胞醛糖还原酶测定荧光法的建立及临床应用[J]. 中国糖尿病杂志, 1999, 7(3) : 154-156.
  
4. 周云平, 张家庆. 醛糖还原酶(AR)的荧光光度法测定及其在糖尿病大鼠晶体AR测定中的应用[J]. 中华内分泌代谢杂志, 1989, 5(3) : 159-161.
5. Shimoshige Y, Ikuma K, Yamamoto T, et al. The effects of zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats[J]. Metabolism, 2000, 49(11) : 1395-1399.
    
6. Suzen S, Buyukbingol E. Recent studies of aldose reductase enzyme inhibition for diabetic complications[J]. Curr Med Chem, 2003, 10(15) : 1329-1352.
    
7. Suh KS, Oh SJ, Woo JT, et al. Effect of cilostazol on the neuropathies of streptozotocin-induced diabetic rats[J]. Korean J Intern Med, 1999, 14(2) : 34-40.
  
8. Ibrahim S, Harris ND, Radata M, et al. A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy[J]. Diabetologia, 1999, 42(6) : 737-742.
    
9. Takahashi K, Ghatei MA, Lam HC, et al. Elevated plasma endothelin in patients with diabetes mellitus[J]. Diabetologia, 1990, 33(5) : 306-310.
    
10. Park JY, Takahara N, Gabriele A, et al. Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation[J]. Diabetes, 2000, 49(7) : 1239-1248.
    
11. Zochodne DW, Cheng C. Diabetic peripheral nerves are susceptible to multifocal ischemic damage from endothelin[J]. Brain Res, 1999, 838(1-2) : 11-17.
    
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