Background Poststroke depression and anxiety, independent predictor of poor functional outcomes, are common in the acute phase of stroke. Up to now, there is no fast-onset antidepressive and anxiolytic agents suitable for the management of acute stroke. ZL006-05, a dual-target analgesic we developed, dissociates nitric oxide synthase from postsynaptic density-95 while potentiates α2-containing γ-aminobutyric acid type A receptor. This study aims to determine whether ZL006-05 can be used as an antistroke agent with fast-onset antidepressant and anxiolytic effects. Methods Photothrombotic stroke and transient middle cerebral artery occlusion were induced in rats and mice. Infarct size was measured by TTC(2,3,5-Triphenyltetrazolium chloride) staining or Nissl staining. Neurological defects were assessed by four-point scale neurological score or modified Neurological Severity Scores. Grid-walking, cylinder and modified adhesive removal tasks were conducted to assess sensorimotor functions. Spatial learning was assessed using Morris water maze task. Depression and anxiety were induced by unpredictable chronic mild stress. Depressive behaviours were assessed by tail suspension, forced swim and sucrose preference tests. Anxiety behaviours were assessed by novelty-suppressed feeding and elevated plus maze tests. Pharmacokinetics, toxicokinetics and long-term toxicity studies were performed in rats. Results Administration of ZL006-05 in the acute phase of stroke attenuated transient and permanent ischaemic injury and ameliorated long-term functional impairments significantly, with a treatment window of 12 hours after ischemia, and reduced plasminogen activato-induced haemorrhagic transformation. ZL006-05 produced fast-onset antidepressant and anxiolytic effects with onset latency of 1 hour in the normal and CMS mice, had antidepressant and anxiolytic effects in stroke mice. ZL006-05 crossed the blood–brain barrier and distributed into the brain rapidly, and had a high safety profile in toxicokinetics and long-term toxicological studies. Conclusion ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy, safety and targeting of clinical issues. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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具有速效抗抑郁和抗焦虑作用的抗中风新药ZL006-05的临床前评价

背景 中风后抑郁和焦虑是功能不良结果的独立预测因素，在中风急性期很常见。迄今为止，还没有适合治疗急性卒中的速效抗抑郁和抗焦虑药物。ZL006-05是我们开发的双靶点镇痛药，可从突触后密度95解离一氧化氮合酶，同时增强含有α2的γ-氨基丁酸A型受体。本研究旨在确定ZL006-05是否可以用作具有快速起效的抗抑郁和抗焦虑作用的抗中风药物。方法在大鼠和小鼠中诱导光血栓性中风和短暂性大脑中动脉闭塞。通过TTC(2,3,5-氯化三苯基四唑)染色或尼氏染色测量梗塞大小。神经系统缺陷通过四分制神经系统评分或改良的神经系统严重程度评分进行评估。进行网格行走、圆柱体和改进的粘合剂去除任务来评估感觉运动功能。使用莫里斯水迷宫任务评估空间学习。抑郁和焦虑是由不可预测的慢性轻度压力​​引起的。通过悬尾、强迫游泳和蔗糖偏好测试来评估抑郁行为。通过新奇抑制喂养和高架十字迷宫测试来评估焦虑行为。在大鼠中进行了药代动力学、毒代动力学和长期毒性研究。结果在中风急性期施用ZL006-05可减轻短暂性和永久性缺血性损伤，并显着改善长期功能损伤，治疗窗口为缺血后12小时，并减少纤溶酶原激活诱导的出血性转化。ZL006-05在正常和CMS小鼠中产生快速起效的抗抑郁和抗焦虑作用，起效潜伏期为1小时，对中风小鼠具有抗抑郁和抗焦虑作用。ZL006-05可穿过血脑屏障并快速分布到大脑中，在毒代动力学和长期毒理学研究中具有较高的安全性。结论 ZL006-05是一种新型神经保护剂，具有快速起效的抗抑郁和抗焦虑作用，在疗效、安全性和针对临床问题方面具有转化特性。可根据合理要求提供数据。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。