低频超声联合尿激酶溶栓治疗大鼠脑梗死的疗效观察

目的 观察低频超声联合尿激酶静脉溶栓治疗大鼠脑梗死的疗效和基质金属蛋白酶9（matrix metalloproteinase-9，MMP-9）及其抑制物1（tissue inhibitor of metalloproteinase-1，TIMP-1）在脑梗死溶栓治疗后的表达。
方法 应用血栓栓塞法制备Wistar大鼠脑梗死模型160只，随机分为尿激酶治疗组、低频超声治疗组、低频超声联合尿激酶治疗组和对照组。进行神经功能缺损评分（Neurological Severity Score，NSS）并测定脑梗死体积，免疫组化观测MMP-9和TIMP-1的表达。
结果 治疗前NSS评分尿激酶治疗组（9.09±1.33）、低频超声治疗组（9.16±1.23）、低频超声联合尿激酶治疗组（9.11±1.45）和对照组（9.28±1.14）比较差异无显著性（F=0.04，P＝0.99），治疗后NSS评分尿激酶治疗组（6.38±1.11）、低频超声治疗组（7.37±1.35）和低频超声联合尿激酶治疗组（5.08±1.31）均低于治疗前（t分别为4.95、3.10和6.52，P均＜0.01）。治疗后梗死灶体积尿激酶治疗组［（59.24±8.25）mm3］、低频超声治疗组［（76.36±9.48）mm3］、低频超声联合尿激酶治疗组［（56.01±9.77）mm3］均低于对照组［（94.90±11.09）mm3］（F=34.06，q=11.63、6.04、12.68；P均＜0.01）。根据治疗方法不同分为尿激酶治疗组和非尿激酶治疗组，两组大鼠脑出血发生率分别为20％、3.75％（校正χ2=8.60，P＜0.01）；低频超声治疗组和非低频超声治疗组，脑出血发生率分别为12.5％、11.25％（χ2=0.06，P＝0.99）。大鼠皮质区MMP-9及TIMP-1在尿激酶治疗组（50.05±6.19，48.24±7.06）、低频超声治疗组（37.45±7.21，43.67±8.12）、低频超声联合尿激酶治疗组（56.77±7.83，55.53±8.86）和对照组（29.23±5.61，33.33±5.79）表达差异有显著性（F=33.44，15.17，P均<0.01），三个治疗组MMP-9及TIMP-1表达均高于对照组（q=9.73，3.84，12.87；q=6.25，4.33，9.30；P均<0.01）。低频超声联合尿激酶治疗组与尿激酶治疗组MMP-9、TIMP-1表达差异有显著性（q=3.14；3.06；P均<0.01）。
结论 低频超声可能具有增强尿激酶溶栓治疗脑梗死的作用，且不增加脑出血的发生。MMP-9及其抑制物TIMP-1在脑梗死尿激酶溶栓和低频超声治疗后的表达均增强。

Effects of Low-frequency Ultrasound Combined with Urokinase Thrombolytic Therapy for Cerebral Infarction in Rats

Objective To observe the effect of low-frequency ultrasound combined with urokinase thrombolytic therapy for cerebral infarction in rats and the expression of matrix metalloproteinase 9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1）. Methods One hundred and sixty cerebral infarction models were divided into 4 groups, including urokinase treatment group, low-frequency ultrasound treatment group, urokinase plus low-frequency ultrasound treatment group and control group. Neurological Severity Score （NSS）, cerebral infarction volume and the expressions of MMP-9 and TIMP-1 were measured. Results The NSS of each group before the treatment （urokinase treatment group 9.09±1.33, low-frequency ultrasound treatment group 9.16±1.23, urokinase plus low-frequency ultrasound treatment group 9.11±1.45 and control group 9.28±1.14） had no signiifcant difference （F=0.04, P=0.99）, but the NSS of three treatment groups after treatment （urokinase treatment group 6.38±1.11, low-frequency ultrasound treatment group 7.37±1.35, urokinase plus low-frequency ultrasound treatment group 5.08±1.31） after treatment were signiifcantly lower than that of before （t=4.95, 3.10, 6.52, P〈0.01）. The infarct volume in each treatment group urokinase treatment group （59.24±8.25）mm3, low-frequency ultrasound treatment group （76.36±9.48）mm3, urokinase plus low-frequency ultrasound treatment group （56.01±9.77）mm3] was significantly lower than that of control group （94.90±11.09）mm3] （F=34.06, q=11.63, 6.04, 12.68;P〈0.01）. The hemorrhagic rate in group with urokinase （20%） was higher than that of group without urokinase （3.75%） （χ^28.60, P〈0.01）. There were no significant differences between the group with low-frequency ultrasound and the group without low-frequency ultrasound in hemorrhagic rates （12.5%vs 11.25%,χ^20.06, P=0.99）. The expressions of MMP-9/TIMP-1 in three treatment groups were signiifcantly higher than that of control group （F=33.44, 15.17, P〈0.01;q=9.73, 3.84, 12.87;q=6.25, 4.33, 9.30;P〈0.01）. The expressions of MMP-9/TIMP-1 in urokinase plus low-frequency ultrasound treatment group were signiifcantly higher than that of urokinase treatment group （q=3.14;3.06;P〈0.01）. Conclusion Low-frequency ultrasound maybe enhance the effect of urokinase thrombolytic therapy for cerebral infarction in rats and have no increased hemorrhagic rate. The expressions of MMP-9 and TIMP-1 increasing after urokinase thrombolytic therapy or low-frequency ultrasound were found.