CN112957453A - 胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用 - Google Patents
胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用。IGFBP2干预可以显著的改善脑外伤引起的焦虑抑郁样行为和脑创伤引起的认知功能下降行为。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用。
背景技术
脑外伤(traumatic brain injury，TBI)是指因外部机械力引起的脑部损伤，如脑部撞击、快速的加减速、声波冲击等，是人类致死致残的主要原因之一。全球每年新增的TBI案例超过数千人次，每年用于脑外伤的治疗费用超过4000亿美元，对个人、家庭乃至社会造成了沉重的负担。严重的TBI除了致死以外，对幸存者也将造成长期而严重的损害，包括身体残疾、情感障碍、认知功能障碍等。其中，脑外伤后引发的精神障碍是常见的长期并发症，严重影响患者的预后。有报道高达56％的TBI患者在创伤后10周出现抑郁症状，此外在中重度的TBI患者中，创伤后第一年的抑郁累积发病率高达53％，相比于普通人群约为7％的发病率显著提高。然而针对创伤后精神障碍，目前并没有有效的干预手段。一项独立的双盲随机安慰剂对照控制的研究中发现舍曲林对TBI后的严重抑郁并没有显著的作用效果，提示了脑外伤后抑郁的复杂性和难治性。脑外伤的病理生理过程以及与TBI相关的抑郁焦虑风险的机制性原因尚不明确是目前仍然缺乏有效的治疗手段的重要原因。
胰岛素生长因子结合蛋白2(IGFBP2)作为IGF结合蛋白中的六大成员之一，是一种具有自分泌和旁分泌的生长因子。研究表明，IGFBP2不仅参与大脑的生长发育，还参与调节神经元的可塑性、调节空间学习记忆和信息处理等高级认知功能。在不可预期应激模型中，IGFBP2通过一种独立于胰岛素生长因子1(IGF1)受体的新机制发挥类似治疗的作用，其长期作用可能是由于对树突棘结构可塑性的促进作用，提示了IGFBP2和类似物可能对应激引起的精神障碍有作用。在中枢神经系统损伤模型中，有研究指出，IGFBP2和IGF1的表达在损伤部位周边显著升高，这提示我们IGFBP2可能对于脑损伤后的精神障碍发挥作用。此外，IGFBP2在中枢系统中广泛存在，并且在发育中的脑中高度表达，在初代星形胶质细胞和神经元中分泌。其在外周中的浓度较低，IGFBP2的分子量为36kD，可以穿过血脑屏障(blood-brain barrier，BBB)。目前并没有相关研究证明IGFBP2可以治疗TBI后的精神障碍。
发明内容
本发明的目的是克服上述现有技术的缺点，提供一种制备治疗脑外伤引起的精神障碍的药物中的应用。
本发明提供的技术方案具体为，胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用。
较佳地，所述的精神障碍包括焦虑抑郁样行为和由于脑创伤引起的认知功能下降行为(认知损伤)。
IGFBP2的干预时间具体为：脑创伤后立即干预。
附图说明
图1为本发明的CCI造模及IGFBP2干预流程示意图。
图2a～2e为IGFBP2干预对动物脑创伤后30天行为学的影响。
图3a～3e为IGFBP2干预对动物脑创伤后60天行为学的影响。
具体实施方式
为了能够更清楚地描述本发明的技术内容，验证IGFBP2在脑外伤(TBI)引起的精神创伤中的作用，下面结合具体实施例来进行进一步的描述。
建立脑损伤小鼠模型
C57小鼠饲养在12小时光照/黑暗节律环境中，可以自由获取水和食物。所有的行为学实验均在动物的光照节律中进行。
首先，利用CCI小鼠造模，将小鼠用异氟烷诱导麻醉后，将小鼠用脑立体定位仪固定，并进行维持麻醉，以(AP+1.5mm，L+1.5mm)为圆心，用颅脑转开一个直径约2mm的窗口，用皮层控制损伤仪进行造模，打击参数为：打击头直径2.0mm、打击深度1.0mm、打击速度2.0m/s、停留时间100ms。损伤完后将颅骨放回并缝合，碘伏消毒后待苏醒，手术过程中应37℃加热垫维持小鼠体温。另外，假手术对照组小鼠用异氟烷诱导麻醉后，将小鼠用脑立体定位仪固定，并进行维持麻醉，以(AP+1.5mm，L+1.5mm)为圆心，用颅脑转开一个直径约2mm的窗口，然后将颅骨放回并缝合，碘伏消毒后待苏醒，手术过程中应37℃加热垫维持小鼠体温。
IGFBP2的干预
手术后，立即进行IGFBP2的干预。干预方式为尾静脉注射，干预剂量为1μg/kg，干预次数为1次。干预后第30天及其第60天进行行为学检测。
具体的CCI造模及IGFBP2干预流程示意图如图1所示。
评价IGFBP2干预效果
通过行为学检测验证IGFBP2对脑创伤后的精神障碍的干预效果。所有的行为学实验均在小鼠光照时间进行。
在行为学实验前，将小鼠放入行为学房间适应2小时。各实验过程中，每完成一只老鼠实验，用70％酒精擦拭，避免气味对下只老鼠的影响。行为学前每天Handle小鼠几分钟，至少适应4天。行为学实验采用了评价抑郁样行为的糖水偏好实验、悬尾实验、强迫游泳实验，评价焦虑样行为的旷场实验和高架十字迷宫实验，以及评价认知行为的新物体识别实验和Barnes迷宫实验。
糖水偏好实验：提前两天进行双瓶适应，一瓶饮用水，一瓶1％的蔗糖。第三天进行检测，检测前动物断水6小时，糖水偏好(％)＝(糖水消耗/(糖水+普通水消耗))*100；悬尾实验：将小鼠尾巴1/3处用胶带固定于支架上，头部悬空，摄像记录6分钟，计算其不动时间。
旷场实验：将实验动物放入50cm X 50cm的箱子中，摄像时间10分钟，计算其在中心区的时间。
高架十字迷宫实验：将小鼠从中央格面向开放臂方向放入十字迷宫，分别记录进入开放臂的次数、停留的时间、进入闭合臂的次数、停留的时间，记录5分钟。Barnes迷宫实验：小鼠进行四天的训练，记录小鼠找到目标洞穴的时间。
ICC造模后30天，通过行为学观察IGFBP2的干预效果，结果如图2a～2e所示。双因素方差分析。双因素方差分析，***代表P<0.001，**代表P<0.001，*代表P<0.05。
如图2a所示，显示旷场实验结果，在假手术动物中，IGFBP2的干预并不会影响其在中心区时间。脑外伤动物在中心区的时间显著低于假手术组，而IGFBP2干预后，脑外伤的动物在中心区的时间显著增加(P<0.0001)。
如图2b所示，显示高架十字迷宫实验结果，脑外伤动物在开放臂的时间要显著低于假手术组。IGFBP2的干预并不会影响假手术组动物在开放臂的时间。但是，IGFBP2的干预显著提高了脑外伤动物在开放臂的时间。
如图2c所示，显示糖水偏好实验结果，脑外伤动物的糖水偏好值显著低于假手术组动物，表现出明显的快感缺失行为。IGFBP2的干预并没有影响假手术组动物的糖水偏好值，但是显著提高了脑外伤动物的糖水偏好值。
如图2d所示，显示悬尾实验结果，脑外伤动物在悬尾实验种不动的时间显著高于假手术组的动物，表现出明显的动力缺失。IGFBP2的干预并没有影响假手术组动物的不动时间，但是显著降低了脑外伤动物的不动时间。
如图2e所示，显示Barnes迷宫实验结果，脑外伤的动物在训练过程种要花费更多的时间去找到洞穴，但是在IGFBP2干预后，脑外伤动物找到洞穴的时间显著降低。
旷场实验和高架十字迷宫实验结果显示IGFBP2可以有效的改善脑外伤引起的焦虑样行为。糖水偏好实验和悬尾实验结果显示IGFBP2干预可以有效地改善脑外伤引起的抑郁样行为。Barnes迷宫实验结果表明IGFBP2干预可以有效的改善脑外伤引起的认知功能障碍。
综上实验数据，支持了IGFBP2干预可以显著的改善脑外伤引起的焦虑抑郁样行为及其认知功能受损。
ICC造模后60天，通过行为学观察IGFBP2的干预效果，结果如图3a～3e所示。双因素方差分析。双因素方差分析，***代表P<0.001，**代表P<0.001，*代表P<0.05。
如图3a～3e所示，60天后，脑创伤的焦虑抑郁样行为和认知障碍行为仍然存在，IGFBP2的干预效果也仍然存在。
综上所述，上述试验验证了IGFBP2干预脑创伤引起的精神障碍的长期效果。
在此说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以作出各种修改和变换而不背离本发明的精神和范围。因此，说明书被认为是说明性的而非限制性的。
Claims (2)
1.胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的精神障碍包括焦虑抑郁样行为和认知下降行为。
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| WO2022183882A1 (zh) * | 2021-03-04 | 2022-09-09 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备治疗成年期应激引起的精神障碍的药物中的应用 |
| WO2023138320A1 (zh) * | 2022-01-21 | 2023-07-27 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备治疗神经脱髓鞘性疾病的药物中的应用 |
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| WO2022183882A1 (zh) * | 2021-03-04 | 2022-09-09 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备治疗成年期应激引起的精神障碍的药物中的应用 |
| WO2022183881A1 (zh) * | 2021-03-04 | 2022-09-09 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备治疗脑外伤引起的精神障碍的药物中的应用 |
| WO2022183883A1 (zh) * | 2021-03-04 | 2022-09-09 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备抗早年应激引起的精神障碍的药物中的应用 |
| CN114137214A (zh) * | 2021-12-06 | 2022-03-04 | 上海市精神卫生中心（上海市心理咨询培训中心） | 用于预测应激后精神心理症状发生的免疫检测试剂盒及应用 |
| CN114137214B (zh) * | 2021-12-06 | 2024-03-01 | 上海市精神卫生中心（上海市心理咨询培训中心） | 用于预测应激后精神心理症状发生的免疫检测试剂盒及应用 |
| WO2023138320A1 (zh) * | 2022-01-21 | 2023-07-27 | 上海市精神卫生中心（上海市心理咨询培训中心） | 胰岛素样生长因子结合蛋白2在制备治疗神经脱髓鞘性疾病的药物中的应用 |
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