【摘要】：目的:1.探討FK506和氯化鋰促進(jìn)大鼠坐骨神經(jīng)損傷后再生的效果及機(jī)制;2.比較使用FK506和氯化鋰在修復(fù)大鼠坐骨神經(jīng)損傷的可行性及優(yōu)越性;3.探討不同劑量FK506和氯化鋰對(duì)坐骨神經(jīng)損傷后修復(fù)和再生的影響及功能恢復(fù)的評(píng)價(jià),為臨床治療周圍神經(jīng)損傷奠定基礎(chǔ)。方法:成年SD大鼠49只,在接受端側(cè)吻合術(shù)后被隨機(jī)分配到7個(gè)不同的組中:A組,7只大鼠均接受腹腔注射0.9%生理鹽水1mg/kg/d;B組,7只大鼠均接受腹腔注射FK506 1mg/kg/d;C組,7只大鼠均接受腹腔注射FK506 0.5mg/kg/d;D組,7只大鼠均接受腹腔注射氯化鋰85mg/kg/d;E組,7只大鼠均接受腹腔注射氯化鋰40mg/kg/d;F組,7只大鼠均接受腹腔注射氯化鋰40mg/kg/d和FK506 0.5mg/kg/d;G組,7只大鼠均接受腹腔注射氯化鋰85mg/kg/d和FK506 1mg/kg/d;手術(shù)后,每天對(duì)大鼠進(jìn)行腹腔內(nèi)注射,共12周。術(shù)后大體觀察實(shí)驗(yàn)大鼠手術(shù)切口、肢體腫脹、肢端潰瘍形成及肢體恢復(fù)自主運(yùn)動(dòng)情況;分別2周、4周、6周、8周和12周進(jìn)行功能學(xué)檢查和分析。術(shù)后12周測(cè)量趾長(zhǎng)伸肌濕重比值、檢測(cè)神經(jīng)電生理、免疫組織化學(xué)指標(biāo)以觀察評(píng)價(jià)神經(jīng)再生和功能恢復(fù)的情況。結(jié)果:1.實(shí)驗(yàn)動(dòng)物數(shù)量及大體觀察實(shí)驗(yàn)選用大鼠49只,高劑量聯(lián)合應(yīng)用FK506和氯化鋰組有2只因免疫抑制劑影響導(dǎo)致死亡,有47只模型進(jìn)入到最終分析。所有大鼠術(shù)后切口均順利愈合,無死亡和感染。少量大鼠見足底潰瘍,均在兩周內(nèi)愈合。術(shù)后早期所有大鼠后肢運(yùn)動(dòng)笨拙,膝關(guān)節(jié)屈曲障礙。術(shù)后第l2周處死前觀察,各使用藥物治療組大鼠的術(shù)側(cè)膝關(guān)節(jié)手術(shù)后屈曲障礙得到了改善明顯,針刺反應(yīng)靈敏。而對(duì)照組改善較差,針刺反應(yīng)較遲鈍。術(shù)前的實(shí)驗(yàn)動(dòng)物的體重之間無統(tǒng)計(jì)學(xué)的差異,然而應(yīng)用藥物治療后實(shí)驗(yàn)組b組、c組、f組、g組動(dòng)物體重明顯低于對(duì)照組有統(tǒng)計(jì)學(xué)差異(p0.05),其中d組licl85mg/kg/d和e組licl40mg/kg/d與對(duì)照組0.9%生理鹽水1mg/kg/d之間無統(tǒng)計(jì)學(xué)差異(p0.05)。(見圖5)2.足印分析結(jié)果術(shù)后第2,4,6,8,10,12周時(shí)進(jìn)行大鼠坐骨神經(jīng)指數(shù)測(cè)量并比較:在各組中,正常步態(tài)的足印(左側(cè)顯示為后爪各趾充分伸展),而術(shù)側(cè)(右側(cè)則顯示為后爪“足下垂”且屈曲攣縮,各趾內(nèi)收)。術(shù)后12周時(shí),6個(gè)藥物治療組sfi與對(duì)照組間比較差異有顯著性意義(p0.05),但是各實(shí)驗(yàn)組之間sfi無明顯統(tǒng)計(jì)學(xué)差異(p0.05)。(見表1)3.趾長(zhǎng)伸肌肌濕重質(zhì)量術(shù)后12周處死大鼠后切取趾長(zhǎng)伸肌,在分析天平上稱出肌肉的濕重并觀察小腿肌肉萎縮情況,并按照如下公式計(jì)算:實(shí)驗(yàn)側(cè)肌肉濕重與正常側(cè)的百分比=實(shí)驗(yàn)側(cè)肌肉重量/對(duì)側(cè)肌肉重量。a組與各實(shí)驗(yàn)組間的差異在統(tǒng)計(jì)學(xué)上有意義(p0.05),實(shí)驗(yàn)組中b組和f組間差異無顯著統(tǒng)計(jì)學(xué)意義(p0.05),但均優(yōu)于其他實(shí)驗(yàn)組(p0.05)。(見表2)4.免疫組織化學(xué)檢測(cè)術(shù)后12周,藥物治療組可見大量再生有髓神經(jīng)纖維和無髓纖維混合,雪旺細(xì)胞形態(tài)正常,包繞再生軸突形成有髓纖維,大多數(shù)髓鞘結(jié)構(gòu)發(fā)育良好,呈同心圓板層樣結(jié)構(gòu),少數(shù)為未完全閉合的不成熟髓鞘。對(duì)照組,可以觀察到再生的神經(jīng)纖維稀疏,髓鞘發(fā)育不良。s100及nf染色,藥物治療組要優(yōu)于對(duì)照組(p0.05),但是各個(gè)藥物之間無統(tǒng)計(jì)學(xué)差異(p0.05)。(見表3,圖3,圖4)5.神經(jīng)電生理檢測(cè)藥物治療組大鼠的神經(jīng)傳導(dǎo)速度上均優(yōu)于空白對(duì)照組,對(duì)照組的神經(jīng)傳導(dǎo)速度第6周和第12周的數(shù)據(jù)上并無好轉(zhuǎn)傾向(p0.05),藥物治療組間兩兩比較后12周的數(shù)據(jù)上均明顯優(yōu)于第6周的數(shù)據(jù)(p0.05)。(見表4)結(jié)論:1.fk506和氯化鋰對(duì)坐骨神經(jīng)損傷的再生都具有明顯的促進(jìn)作用。2.長(zhǎng)期小劑量聯(lián)合應(yīng)用fk506和氯化鋰處理后可在短時(shí)間內(nèi)降低周圍神經(jīng)損傷后發(fā)生的免疫排斥反應(yīng),從而迅速改善坐骨神經(jīng)損傷后再生的微環(huán)境,以利于神經(jīng)再生速度和質(zhì)量的提高,取得了與高劑量聯(lián)合用藥組同樣的治療效果,卻并沒有發(fā)生致命的不良反應(yīng),對(duì)于臨床應(yīng)用免疫抑制劑有潛在的意義。
[Abstract]:Objective: 1. to investigate the effect and mechanism of FK506 and lithium chloride to promote the regeneration of sciatic nerve injury in rats; 2. compare the feasibility and superiority of using FK506 and lithium chloride in Repairing Sciatic nerve injury in rats; 3. to explore the effect of different doses of FK506 and lithium chloride on the repair and regeneration of sciatic nerve injury and the evaluation of functional recovery. Methods: 49 adult SD rats were randomly assigned to 7 different groups after receiving end to side anastomosis: group A, 7 rats received intraperitoneal injection of 0.9% physiological saline 1mg/kg/d; B group, 7 rats received intraperitoneal injection of FK506 1mg/kg/d; group C, and 7 rats received FK506 0.5mg/kg/d in abdominal cavity; D group, all rats. 7 rats were treated with intraperitoneal injection of lithium chloride 85mg/kg/d; in group E, 7 rats were injected with lithium chloride 40mg/kg/d intraperitoneally; group F, 7 rats received intraabdominal injection of lithium chloride 40mg/kg/d and FK506 0.5mg/kg/d; group G, and 7 rats were intraperitoneally injected with lithium chloride 85mg/kg/d and FK506 1mg/kg/d; after the operation, intraperitoneal injection of rats was carried out every day, After 12 weeks, the surgical incision, limb swelling, acromegaly ulcers and limb recovery were observed and the functional examination and analysis were carried out for 2 weeks, 4 weeks, 6 weeks, 8 weeks and 12 weeks respectively. The wet weight ratio of the extensor digitorum longus was measured at 12 weeks after the operation, and the neuroelectrochemistry and immunohistochemistry were measured to evaluate the nerve regeneration and the evaluation of nerve regeneration. Results: 1. the number of experimental animals and the gross observation were 49 rats. High dose combined use of FK506 and lithium chloride group were killed by immunosuppressive agents. 47 models entered the final analysis. All the rats were successfully healed after operation, without death and infection. A small amount of rats saw foot ulcers, all of which were found in the rats. After two weeks, all rats' hind limbs were clumsy and knee flexion disorders. After the operation L2 weeks after the operation, the flexion disorders were improved obviously after operation side knee joint operation in the drug treatment group, and the acupuncture reaction was sensitive. The control group was less improved and the acupuncture reaction was slow. The body of the experimental animals before the operation. There was no statistical difference between weight, but the body weight of B group, C group, F group and G group was significantly lower than that of control group (P0.05), among which there was no statistical difference between D group licl85mg/kg/d and E group licl40mg/kg/d and control group 0.9% physiological saline 1mg/kg/d (P0.05). (see figure 5) 2. foot print analysis of postoperative 2,4,6 At 8,10,12 weeks, the sciatic nerve index of rats was measured and compared: in each group, the foot prints of normal gait (the left side of the hind paw were fully extended), while the operation side (the right side was displayed as the hind paw "foot droop" and the flexion contracture, and the adduction of the toes). The difference between the SFI and the control group was significant 12 weeks after the operation (P 0.05) but there was no significant difference in SFI between the experimental groups (P0.05). (see Table 1) the muscle wet weight of the 3. toed extensor muscle after 12 weeks after the operation of the muscle wet weight of the extensor muscle of the 3. toes was taken and the muscle atrophy of the leg was observed and the muscle atrophy of the calf was observed. The difference between the lateral muscle weight and the contralateral muscle weight.A group and the experimental group was statistically significant (P0.05). There was no significant difference between the group B and the F group in the experimental group (P0.05), but it was better than the other experimental groups (P0.05). (see Table 2) 12 weeks after the 4. immunohistochemical examination, a large number of regenerated myelinated nerve fibers were found in the drug treatment group. Mixed with unmyelinated fibers, the morphology of Schwann cells is normal and surrounds the regeneration axon to form myelinated fibers. Most of the myelin sheath is well developed, with a concentric circular plate like structure and a few unfully closed immature myelin sheath. The control group can observe the sparsity of the regenerated nerve fibers, the myelin dysplasia.S100 and NF staining. The drug treatment group is superior to the control group. In the control group (P0.05), there was no statistical difference between each drug (P0.05). (see Table 3, figure 3, figure 4) 5. the nerve conduction velocity of rats in the neuroelectrophysiological test group was superior to that of the blank control group. The nerve conduction velocity of the control group had no improvement on the data of sixth weeks and twelfth weeks (P0.05), and 22 of the drug treatment groups were compared. The data on the following 12 weeks were significantly better than that of sixth weeks (P0.05). (see Table 4) conclusion: 1.fk506 and lithium chloride have an obvious promoting effect on the regeneration of sciatic nerve injury..2. long-term small dose combined with FK506 and lithium chloride treatment can reduce the immune rejection in a short time after the injury of the surrounding deity. The regenerated microenvironment after the injury of the sciatic nerve is beneficial to the improvement of the speed and quality of nerve regeneration. It has obtained the same therapeutic effect as the high dose combination group, but has no fatal adverse reaction. It is of potential significance for the clinical application of immunosuppressive agents.
【學(xué)位授予單位】：承德醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R651.3

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