The Anti-anxiety Effect And Mechanism Of ZL006-05

Anxiety is defined as the manner of regulating the response of an animal to potentially threatening or threatening stimuli,whereas excessive anxiety will become the pathological anxiety.Patients with anxiety disorders are mainly charactered by abnormal mood such as worry,fear,nervous or the feeling of disaster approaches.Normal anxiety can increase the body's defensive consciousness,to reduce or avoid damage.And excessive anxiety have a negative impact on People's daily life,social communication and work.Available clinical treatments are addictive or,in the case of benzodiazepines,inconsistently effective and connected to significant side effects including respiratory suppression and cognitive impairment.Therefore,it is imminent to find anxiolytics with higher safety,less side effect and better treatment.Studies have shown that N-methyl-N-aspartate(N-methyl-D-aspartate,NMDA)mainly distributed in the postsynaptic receptor,mediated excitatory signal transmission and adjusted neural synaptic plasticity.Ketamine can directly block NMDA receptors,produce strong anti-anxiety effects.However,the use of ketamine can bring huge psychological stimulation to patients and the risk of insanity.Therefore,the indirect block the NMDA receptor and NMDA receptor partial antagonism have become a hot spot among scientists.Neuronal nitric oxide synthase(nNOS)is widely expressed in neurons.The PDZ of nNOS connected with density protein 95(post-synaptic density protein 95,PSD-95)forming nNOS-PSD-95 compounds.PSD-95 is a kind of synaptic proteins,which can mediate synaptic plasticity,adjust dendritic spines and synaptic stability.In the postsynaptic membrane,nNOS and PSD-95 coupling can also adjust the formation of synapses and neuron death causing by the NMDA receptor.Currently nNOS-PSD-95 small molecules decoupling including ZL006 and IC87201.The study in rodents,mice given ZL006 or IC87201 has a significant antidepressant effect,but has no effect on the anxiety behavior.The research object of this article is ZL006-05.ZL006-05 is synthetised by ZL006 and(+)-Borneol through ester linkage connection.The present study shows ZL006 has significant neural protection and promotes the regeneration of the neurons after cerebral stroke.Previous studies have shown that Borneol can enhance GABA evoked current,which has good effect in pain.So,we want to study whether ZL006-05 will influence the anxiety behavior in normal mice and the mice experienced chronic unpredictable stress(CUS).And if ZL006 and Borneol play a role in this process respectively.In order to verify the assumption,threes parts in the article will be explored.Part ? To evaluate anxiolytic-like effect of ZL006-05,ZL006-05 was delivered to mice by gastric gavage.Then anxiety-related behaviors test were examed 1 hour or 24 hours later.One hour after administration of ZL006-05,mice significantly increases the time in the open armies in EPM and lit side in LDB.In the OFT test,ZL006-05 have no effect on the activity among these groups.To study ZL006-05 impact on the pathological models,we validated the reliability of the CUS model first.7 days after CUS,the anxiety level of mice still maintain at a high level.Then,we found that ZL006-05 caused normal mice display an rapid anti-anxiety effect,similar result was observed in CUS mice.Also,continuous administration with ZL006-05 can improve the performance of CUS mice in anxiety-related behavior.Part ? To verify the role of Borneol and ZL006 in anxiolytic effect of ZL006-05.Firstly,Borneol was administrated in normal mice and CUS mice.Borneol has rapid anxiolytic effect in both normal and CUS mice and continuous administration with Borneol also has anxiolytic effect.However,the anxiolytic effect of Borneol vanished a week after continuous drug administration.And the ZL006 was administrated in normal mice and CUS mice.In normal mice,ZL006 has no influence on the anxiety-related behavior in mice.In CUS mice,ZL006 can not produce rapid anxiolytic effect.However,continuous administration with ZL006 obviously improve the performance of CUS mice in anxiety-related behavior and the improvement can continue for some time.Part ? To verify the role of Borneol in anxiolytic effect of ZL006-05,To further study about the mechanism underlying the effect of borneol,whole-cell recording of the hippocampus pyramidal cell found that GABA and borneol application can significantly improve GABA-evoked current amplitude.Then,we explore the mechanism underlying observed phenomenon generated by ZL006.First we detected the protein expression of spinophilin and synapsin by WestBlotting,found that the protein expression of spinophilin and synapsin decreases in hippocampus and continuous administration with ZL006 can reverse this phenomenon.In order to further validate the effect of ZL006 on anxiety-related behavior,we injected LV-nNOS-N1-133-GFP virus into hippocampal DG area of CUS mice.Two weeks later,we found that mice application with the virus perform better than LV-GFP group.In conclusion,borneol havs significant rapid anti-anxiety effect and this effect could be caused by enhancing GABA-evoked current amplitude.ZL006 can ameliorate hippocampal synaptic plasticity caused by CUS so as to bring about an anxiolytic effect on CUS mice.And the advantage of ZL006 and borneol on anxiety-related behavior can be found in ZL006-05.Therefore,ZL006-05 may become one of novel anxiolytics.