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Preclinical evaluation of ZL006-05, a new antistroke drug with fast-onset antidepressant and anxiolytic effects

医学 药品 抗焦虑药 抗抑郁药 药理学 心理学 焦虑 精神科
作者
Hai‐Yin Wu,Zhen-Quan Huang,Xuan Wang,Mingyu Chen,Wei Chen,Hua Yang,Jian Ren,Luyao Shen,Yixuan Song,Ying Zhou,Chunxia Luo,Lin Yang,Yilong Wang,Lei Chang,Fēi Li,Dong‐Ya Zhu
出处
期刊:Stroke and vascular neurology [BMJ]
卷期号:8 (6): 463-474 被引量:3
标识
DOI:10.1136/svn-2022-002156
摘要

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.
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