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

Abstract

BackgroundPoststroke 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.MethodsPhotothrombotic 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.ResultsAdministration 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.ConclusionZL006-05 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.

Intracalvariosseous injection bypasses the blood-brain barrier as a novel drug delivery approach for pre-clinical and clinical trials in stroke

“…Disinfection to drilling time 19 (14,33) Disinfection to injection time 22 (16,36) Disinfection to the end time 32 (22,48) Drilling to injection time 3 (2,10) Median detail time of operations without drilling (range), min…”

“…Preclinical studies have demonstrated that administering NA1/Y-3 during the acute stage of stroke can minimize temporary and permanent damage [21][22][23][24] . After 24 hours of administration, the brain tissue was stained with TTC to label the area of brain infarction.…”

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

“…67 ZL006-05 (6, Figure 2) is a hybrid from 5 and borneol. 25 Treatment with 6 during the acute phase of IS significantly reduced both transient and permanent ischemic injury. It also improved long-term neuronal function, with a therapeutic window of 12 h after the onset of IS.…”

“…Interestingly, 6 reduced plasminogen activation-induced hemorrhagic transformation and exhibited antidepressant and anxiolytic effects in mice with stroke. 25 Additionally, 6 could penetrate the BBB and quickly distribute into the brain, and showed a high safety profile in toxicokinetics and long-term toxicological studies. 25 Compound 6 accessed to clinical phase II trial (CTR20231033) in China in 2023.…”

“…25 Additionally, 6 could penetrate the BBB and quickly distribute into the brain, and showed a high safety profile in toxicokinetics and long-term toxicological studies. 25 Compound 6 accessed to clinical phase II trial (CTR20231033) in China in 2023.…”