CN108498496B - 亮蓝g在制备急性co中毒的治疗药物中的应用 - Google Patents
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Abstract
本发明公开了亮蓝G在制备急性CO中毒的治疗药物中的应用,实验证明:采用亮蓝G对急性CO中毒的大鼠进行腹腔注射,发现亮蓝G能够明显降低ACMP引起的大鼠死亡率,减轻ACMP大鼠海马组织的水肿情况,降低炎症反应,提高学习记忆功能,亮蓝G对急性CO中毒的海马组织具有保护作用,有利于提高ACMP的预后生存质量,为临床研究治疗CO中毒的新药物提供新的思路。
Description
技术领域
本发明涉及急性CO中毒的救治领域,具体是亮蓝G在制备急性CO中毒的治疗药物中的应用。
背景技术
一氧化碳中毒是含碳物质燃烧不完全时的产物经呼吸道吸入引起中毒。中毒机理是一氧化碳与血红蛋白的亲合力比氧与血红蛋白的亲合力高200-300倍,所以一氧化碳极易与血红蛋白结合,形成碳氧血红蛋白,使血红蛋白丧失携氧的能力和作用,造成组织窒息。对全身的组织细胞均有毒性作用,尤其对大脑皮质的影响最为严重。临床表现主要为缺氧,其严重程度与HbCO的饱和度呈比例关系。轻者有头痛、无力、眩晕、劳动时呼吸困难,HbCO饱和度达10%-20%。症状加重,患者***呈樱桃红色,可有恶心、呕吐、意识模糊、虚脱或昏迷,HbCO饱和度达30%-40%。重者呈深昏迷,伴有高热、四肢肌张力增强和阵发性或强直性痉挛,HbCO饱和度大于50%。患者多有脑水肿、肺水肿、心肌损害、心律失常和呼吸抑制,可造成死亡。
亮蓝G(又称BBG)是P2X7R的特异性拮抗剂,在用于研究P2X7R在疾病中扮演的角色的体内实验中扮演着重要作用,亮蓝G已经成为使用最广泛的拮抗剂。近几年研究证明亮蓝G对许多脑部疾病有神经保护作用。亮蓝G的干预可以减轻阿兹海默病,脊柱损伤,脑缺血引起的神经症状和病理结果。而ACMP引起的脑损伤机制不明,治疗手段单一,患者预后迟发型脑病发病率高,但是亮蓝G对ACMP的影响未见相关研究.
发明内容
本发明的目的在于提供一种亮蓝G在制备急性CO中毒的治疗药物中的应用,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
亮蓝G在制备急性CO中毒的治疗药物中的应用。
作为本发明进一步的方案:亮蓝G的使用剂量为26-38mg/kg。
与现有技术相比,本发明的有益效果是:本发明采用亮蓝G对CO中毒的大鼠进行腹腔注射,发现亮蓝G能够明显降低ACMP引起的大鼠死亡率,减轻ACMP大鼠海马组织的水肿情况,降低炎症反应,提高学习记忆功能,亮蓝G对急性CO中毒的海马组织具有保护作用,有利于提高ACMP的预后生存质量,为临床研究治疗CO中毒的新药物提供新的思路。
附图说明
图1为亮蓝G在制备急性CO中毒的治疗药物中的应用中腹腔注射不同剂量的CO气体后大鼠6h内HbCO浓度的变化,n=10的示意图。
图2为亮蓝G在制备急性CO中毒的治疗药物中的应用中BBG对于海马组织促炎因子IL-1β的影响图。
图3为亮蓝G在制备急性CO中毒的治疗药物中的应用中BBG对于海马组织促炎因子TNF-ɑ的影响图。
图4为亮蓝G在制备急性CO中毒的治疗药物中的应用中BBG对于海马组织促炎因子IL-6的影响图。
图5为亮蓝G在制备急性CO中毒的治疗药物中的应用中BBG减轻海马组织含水量的增加的影响图。
图6为亮蓝G在制备急性CO中毒的治疗药物中的应用中定位航行训练的曲线图。
图7为亮蓝G在制备急性CO中毒的治疗药物中的应用中定位航行训练的柱状图。
图8为亮蓝G在制备急性CO中毒的治疗药物中的应用中空间探索实验的结果图。
图9为亮蓝G在制备急性CO中毒的治疗药物中的应用中空间探索实验的轨迹图。
图10为亮蓝G在制备急性CO中毒的治疗药物中的应用中200倍下一氧化碳中毒后3天海马CA1区神经细胞损伤图。
图11为亮蓝G在制备急性CO中毒的治疗药物中的应用中大鼠染毒6h后ACMP组海马组织P2X7R的变化图。
具体实施方式
下面结合具体实施方式对本专利的技术方案作进一步详细地说明。
注射不同剂量的CO气体后结果显示:腹腔注射70ml/kg的CO气体时,大鼠死亡率为0,注射100ml/kg CO气体时,大鼠的死亡率为50%,而注射150ml/kg CO气体时,大鼠死亡率为100%。表明,ACMP后大鼠的死亡率对腹腔注射的CO气体剂量有浓度依赖性,选取死亡率为45%的剂量为最佳造模剂量,即腹腔注射CO气体剂量为100ml/kg。见表1。
表1腹腔注射不同剂量CO气体后动物的死亡率
剂量/ml/kg | 数量/只 | 死亡数/只 | 死亡率/% |
70 | 10 | 0 | 0 |
100 | 10 | 5 | 50 |
150 | 10 | 10 | 100 |
腹腔注射不同剂量的气体CO,检测0.5h;2h;6h HbCO血红蛋白浓度结果显示:除对照组外,其余三组均在注射CO气体30min后出现HbCO蛋白浓度上升,1~2小时达高峰,然后逐渐下降,注射70ml/kg的CO气体30min后大鼠HbCO浓度最高达到67.5%,染毒后6h降至23.43%。注射100ml/kg的CO气体HbCO浓度最高达到80.7%,染毒后6h降至26.78%。注射150ml/kg的CO气体HbCO浓度最高达到89.97%,染毒后6h仍然居高不下,见图1。
注射不同剂量气体CO后,综合大鼠死亡比例和HbCO的浓度的结果,选择100ml/kg做为造模浓度是最佳选择,既能保证实验动物的存活量,又最接近现实CO中毒后HbCO的变化趋势。
腹腔注射CO气体10min之后,部分大鼠出现烦躁不安,四肢无力,呼吸急促,走路不稳,嗜睡,昏睡等症状。2h时症状最为严重,死亡率也最高,大鼠出现四肢无力,行走困难,四肢及口角等裸露处皮肤呈樱桃红色,解剖死亡大鼠发现其内脏充血水肿,肺呈粉红色。
实施例1
一种亮蓝G在制备急性CO中毒的治疗药物中的应用,具体步骤如下:
步骤一,选择80只8-10周龄的大鼠并且随机平均分为Control组、ACMP组、ACMP+亮蓝G组、亮蓝G组,然后向大鼠腹腔注射不同剂量的CO来制备大鼠ACMP模型,注射CO的剂量为100ml/kg;
步骤二,向ACMP+亮蓝G组和亮蓝G组的大鼠注射亮蓝G,亮蓝G的注射剂量为30mg/kg,检测静脉血中的HbCO浓度来判断CO中毒程度,采用RT-PCR法检测大鼠海马组织P2X7RmRNA的表达,采用干湿称重法检测海马组织水肿程度,采用ELISA法检测海马组织IL-1β、TNF-ɑ、IL-6促炎因子的含量,HE染色观察海马CA1区细胞形态学改变,采用Morris水迷宫实验评价学习记忆能力。
结果发现:第一,Control组和亮蓝G组存活率都是100%,而ACMP组的存活率为55%,明显低Control组(P<0.05);ACMP+亮蓝G组的存活率为75%,较ACMP组有明显提高(P<0.05),可以得出亮蓝G可以减少ACMP引起的大鼠死亡率。
第二,用ELISA方法检测四组大鼠海马组织促炎因子IL-1β,IL-6和TNF-ɑ的含量,与Control组和亮蓝G组相比,ACMP组的IL-1β、IL-6,TNF-ɑ的含量明显升高(P<0.05)。与ACMP组相比,ACMP+亮蓝G组的IL-1β,TNF-ɑ和IL-6显著降低(P<0.05)。与Control组相比,亮蓝G组的炎症因子IL-1β,IL-6和TNF-ɑ略低,但没有统计学意义。可见亮蓝G预处理能够有效的抑制CO诱导海马组织促炎因子的释放,见图2-4。
第三,干湿称重法检测海马组织含水量。Control组和亮蓝G组的海马组织含水量分别为79.22%±0.82%和78.97%±0.71%,两者之间无显著差异。ACMP组海马组织含水量为80.72%±0.93%,明显高于Control组(P<0.05)。而ACMP+亮蓝G组海马组织含水量为79.56%±0.63%,显著低于ACMP组(P<0.05)。证明亮蓝G预处理可以明显改善ACMP引起的海马组织水肿,见图5。
第四,进行定位航行训练7天,结果显示:全部大鼠的逃避潜伏期第1天平均为46.25s,第7天降至14.02s,且四组之间均无显著差(P>0.05),见图6-A。第8天对各组大鼠进行相应药物处理后发现亮蓝G组与Control组之间的逃避潜伏期无统计学差异,ACMP组的逃避潜伏期较Control组显著延长(P<0.05),而ACMP+亮蓝G组的逃避潜伏期明显短于ACMP组(P<0.05);进行空间探索实验,结果显示:亮蓝G组与Control组相比,在目标象限的探索时间无统计学差异,与Control组相比,ACMP组的大鼠在目标象限的探索停留时间显著缩短(P<0.05),轨迹减少,与ACMP组相比,ACMP+亮蓝G组的大鼠在SE象限的探索时间明显延长(P<0.05),轨迹增加。证明亮蓝G预处理可以改善ACMP造成的大鼠学习记忆能力的减退,见图6-9。
第五,HE染色法检测四组大鼠海马CA1区神经细胞的形态结构变化,结果显示:Control组的细胞密集整齐排列,胞体形态规整,胞质丰富,胞核与胞质界限清晰可见;ACMP组海马CA1区细胞数目减少,细胞排列紊乱,细胞形态不完整,胞质稀少,胞核与胞质界限模糊,细胞核深染、固缩,呈三角形或不规则形。与ACMP组比较,亮蓝G+ACMP组大鼠海马CA1区神经细胞核固缩现象明显改善,形态较规则,排列整齐。亮蓝G组与Control组无明显差异。结果显示亮蓝G预处理能够改善急性CO中毒引起的大鼠海马CA1区神经元损伤。适宜浓度的亮蓝G单独处理,对大鼠海马神经元CA1区的形态结构无影响,见图10。
第六,RT-PCR结果显示,ACMP组海马组织的P2X7R mRNA的表达量比Control组有明显的增高(P<0.01),ACMP+BBG组的P2X7R mRNA的表达量比ACMP组明显降低(P<0.05),BBG组与Control组没有统计学差异,见图11。
对于本领域技术人员而言,显然本发明不限于上述示范性实施例的细节,而且在不背离本发明的精神或基本特征的情况下,能够以其他的具体形式实现本发明。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围由所附权利要求而不是上述说明限定,因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。不应将权利要求中的任何附图标记视为限制所涉及的权利要求。
此外,应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
Claims (3)
1.亮蓝G在制备急性CO中毒的治疗药物中的应用。
2.权利要求1所述的亮蓝G在制备急性CO中毒的治疗药物中的应用,其特征在于,所述亮蓝G的使用剂量为26-38mg/kg。
3.权利要求2所述的亮蓝G在制备急性CO中毒的治疗药物中的应用,其特征在于,所述亮蓝G的使用剂量为30mg/kg。
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急性一氧化碳中毒家兔红细胞微观血流变学变化及其意义的探讨;王喜福等;《中国工业医学杂志》;20101031;第23卷(第5期);第323-326页 * |
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