摘要
目的探讨基质金属蛋白酶(MMP)抑制剂GM6001对细菌性脑膜炎的脑保护作用。方法①短期治疗实验大鼠小脑延髓池穿刺注入1μl肺炎链球菌菌悬液,制备脑膜炎模型;头孢曲松组大鼠造模后24 h开始sc给予头孢曲松100 mg.kg-1,共2 d;头孢曲松+GM6001组大鼠制备模型后24 h sc给予头孢曲松100 mg.kg-1和ip给予GM6001 65 mg.kg-1共2 d;72 h后观察症状表现,检测脑含水量,测定脑脊液MMP酶活性,并进行脑组织病理学检查。②长期治疗实验分组给药和造模同短期治疗实验,给药共14 d;3周后行Morris水迷宫行为测试。结果①短期治疗实验与正常对照组相比,脑膜炎模型组,头孢曲松和头孢曲松+GM6001组大鼠症状评分明显增加,从0分别增加到(5.0±0.24)(,2.1±0.52)和(1.3±0.23)分(P<0.01);与模型组相比,头孢曲松和头孢曲松+GM6001组相比症状明显减轻(P<0.01);与正常对照组相比,模型组、头孢曲松组和头孢曲松+GM6001组MMP-9酶活性也显著升高,从36±24分别升高到1264±98,602±48和405.8±59.8(P<0.01);与模型组相比,MMP-9酶活性头孢曲松组和头孢曲松+GM6001组显著降低(P<0.01)。病理检查发现,模型组大鼠蛛网膜下腔明显扩张,充满大量炎性细胞,血管高度扩张充血,海马和皮质神经元均出现损伤表现;与模型组相比,头孢曲松组和头孢曲松+GM6001组MMP-9酶活性,海马神经元数目97±23分别增加到112±5和125±18(P<0.01),皮质神经元数目由129±21分别增加到142±8和157±24(P<0.01);脑组织含水量分别由(49.2±1.2)%下降到(48.6±0.8)%和(47.2±1.3)%(P<0.01)。②长期治疗实验与正常对照组相比,模型组Morris水迷宫行为测试大鼠到达平台时间由23±6延长到(49±9)s(P<0.01);与脑膜炎模型组相比,经头孢曲松和头孢曲松+GM6001长期治疗14 d后,Morris水迷宫行为测试大鼠到达平台时间则从49±9明显缩短到33±8和(40±8)s(P<0.01)。结论基质金属蛋白酶抑制剂GM6001能减轻肺炎链球菌性脑膜炎脑组织的水肿,减少神经元死亡,提高大鼠空间记忆能力,具有神经保护作用。
OBJECTIVE To investigate the role of matrix metalloproteinase（MMP） inhibitor GM6001 in neuroprotection against pneumococcal meningitis.METHODS The experiment was divided into a short-term experiment for 2 d and a long-term experiment for 14 d,which was divided into normal control,meningitis model,ceftriaxone and ceftriaxone＋GM6001 groups.A meningitis model was induced by intracisternal injection with 1 μl Streptococcus pneumoniae.Rats in coftriaxone group were sc given ceftriaxone 100 mg·kg-1 at 24 h after model induction,and rats in coftriaxone＋GM6001 group were sc given ceftriaxone 100 mg·kg-1 and ip given GM6001 65 mg·kg-1 for 2 d.Symptoms of rats were observed.MMP-9 activity was detected by SDS-PAGE.Their brain was weighed by electrolight analytical balance.Morphologic changes in cortical and hippocampal neurons were observed with HE staining.Semiquantitative analysis of cortical and hippocampal neurons was carried out using Nissl stain.The spacial memory was examined by Morris water maze in rats.RESULTS During the short-term experiment,compared with normal control group,the symptom score and MMP-9 activity in meningitis model and ceftriaxone groups increased from 0 to 5.0±0.24,2.1±0.52 and from 35.7±24.1 to 1264.1±98.5,602.5±48.3,respectively（P0.01）.After ceftriaxone＋GM6001 for 2 d,the symptom score decreased to 1.3±0.23（P0.01）,subarachnoid space was enlarged and filled with granulocytes and subarachnoid vessels marked dilation in meningitis model group.Arrangement of cortical and hippocampal neurons was in disordery,in obvious loss of hippocampal and cortical neurons was observed in meningitis model group.Compared with normal control group,the cell number of hippocampus and cortex in model group was siginificantly decreased（P0.01）.Compared with model group（97±23,129±21）,the cell number of hippocampus and cortex in ceftriaxone＋GM6001 group increased to 125±18 and 157±24,respectively（P0.01）.Compared with normal control gorup,brain water contents in model group increased from（45.9±1.6）% to（49.2±1.2）%（P0.01）.After ceftriaxone＋GM6001 for 2 d,brain water contents decreased to（47.2±1.3）%（P0.01）.During the long-term experiment,compared with normal control group,the latency to the platform in model group,was significantly prolonged from 22.8±5.5 to（48.7±9.3）s（P0.01）.Compared with model group,mean latency to the platform was shorter 42.8±5.5 and（39.5±7.6） s in ceftriaxone and ceftriaxone＋GM6001groups（P0.05）.CONCLUSION GM6001 attenuates cerebral edema,lessens neuronal death and improves learning ability of rats,thus GM6001 may be neuroprotective for rats with pneumococcal meningitis.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2011年第2期156-161,共6页
Chinese Journal of Pharmacology and Toxicology
基金
2010年山东省科技攻关计划项目(2010GSF10262)
济南市高校自主创新计划项目(201004057)~~
