Therapeutic Potential And Mechanisms Underlying The Antidepressant-like Effects Of A Novel AMPA Receptor Activator PF-4778574

Objectives: Depression is an extremely prevalent mental illness which can recur frequently in an individual.It is often associated with a high suicide rate and other characteristic,and is one of the major problems threatening the physical and mental health of humans and increasing their social and economic burden.At present,conventional antidepressants have a slow onset of action and cause a variety of side effects;thus,the development of rapid-acting antidepressants is imperative.The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor(AMPAR)is an excitatory ionotropic glutamate acid receptor that mediates rapid excitatory synaptic transmission in the central nervous system,promoting neurodevelopment and synaptic plasticity.PF-4778574 is a positive allosteric modulator of AMPA receptors.However,whether PF-4778574 can activate AMPA receptors and elicit antidepressive effects has not been elucidated yet.In this study,using a chronic unpredictable stress(CUS)paradigm,we investigated the mechanisms underlying the antidepressant effect of PF-4778574.Additionally,we studied the molecular changes occurring upon PF-4778574 administration.The purpose of this study was to elucidate the molecular mechanism underlying the antidepressant effects of PF-4778574 in order to understand its therapeutic potential.Methods: Adult ICR male mice,aged 5 to 6 weeks,were used to establish a model of depression.The following tests were used to investigate the changes in locomotor activity and depression-like behavior after drug intervention: open-field test,forced swimming test,sucrose preference test,and novelty suppressed feeding test.The underlying biochemistry was studied using a combination of western blotting and immunopathology.Results: The study shows that a single dose of PF-4778574(1 mg/kg)and PF-4778574(2 mg/kg)exposure significantly reversed CUS-induced depression-like behaviors.Furthermore,it led to a decrease in the expression of membrane AMPAR subunit 1,total AMPAR subunit 1,brain-derived neurotrophic factor(BDNF),VGF(non-acronymic),phosphorylated tropomyosin-related kinase B(pTrkB),phosphorylated protein kinase B(protein kinase B,PKB,also known as AKT),post-synaptic density protein 95(PSD95)and synapsinⅠ in the prefrontal cortex(PFC)of mice.These results indicate that PF-4778574 can produce a rapid anti-depressant effect.In addition,this effect could last one week with no significant change in autonomic activity;However,the pharmacological block of AMPAR by NBQX infusion into the lateral ventricles of the brain significantly abolished these effects of PF-4778574,These data confirm that the antidepressant effects of PF-4778574 are mediated by the modulation of AMPA receptors.Furthermore,PF-4778574 promotes the protein expression of BDNF and VGF,activates the TrkB / AKT signaling pathway,and promotes synaptic development.Furthermore,we found that the rapid antidepressant-like effects of PF-4778574 were completely blocked by verapamil,which indicates that L-type calcium channels play an important role in this effect.PF-4778574 can also reverse the depression-like behavior and the down-regulation of AMPA receptor subunit,BDNF,and neuropeptide VGF protein expression in the PFC induced by Chicago sky blue 6B and vesicular glutamate transporter(VGLUT1)knockdown.Conclusions: This study confirmed the rapid antidepressant effect of PF-4778574,a positive allosteric modulator of the AMPA receptor,and found that this antidepressant effect lasts for one week.Moreover,theactivation of AMPA receptors,the TrkB / AKT signaling pathway,and the release of BDNF and VGF were found to be involved in the rapid antidepressant effect elicited by PF-4778574.In addition,PF-4778574 reversed the depression symptoms caused by Chicago sky blue 6B and VGLUT1 knockdown.This study provides a theoretical basis for further investigation of antidepressant drugs targeting AMPA receptors.