Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist inhibits apoptosis of retinal ganglion cells in a rabbit model of optic nerve injury

A rabbit model of traumatic optic nerve injury, established by occlusion of the optic nerve using a vascular clamp, was used to investigate the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist GYKI 52466 on apoptosis of retinal ganglion cells following nerve injury. Hematoxylin-eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that retinal ganglion cells gradually decreased with increasing time of optic nerve injury, while GYKI 52466 could inhibit this process. The results demonstrate that following acute optic nerve injury, apoptosis of retinal ganglion cells is a programmed process, which can be inhibited by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist.

Role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor regulation in stress-induced pain chronification

Persistent postsurgical pain is a serious issue in public health, which has received increased interest in recent years. Previous studies have reported that psychological factors promote the development of chronic postsurgical pain. However, it is unclear how chronification of postsurgical pain occurs. The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor(AMPA) phosphorylation in the central nervous system plays a critical role in synaptic plasticity and contributes to central sensitization and chronic pain development. Here, we discuss the role of AMPA receptor regulation in stress-induced pain chronification after surgery.

An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives catalyzed by tungstate sulfuric acid

An efficient three-component synthesis of 6-amino-4-aryl-5-cyano-3-metriyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles via a reaction between 3-methyl-1-phenyl-2-pyrazolin-5-one,aromatic aldehydes and malononitrile using tungstate sulfuric acid as a catalyst was described.Mild conditions,good to excellent yields,easily available catalyst and easy work-up are the key features of this method.

Clinical features of AMPAR2 antibody-positive autoimmune encephalitis with gastrointestinal hemorrhage: a case report

Objective:To describe the clinical features of autoimmune encephalitis complicated with gastrointestinal hemorrhage.Methods:The clinical data of one patient whose initial symptom was mental abnormality were collected and the related examinations,such as cerebrospinal fluid and magnetic resonance imaging (MRI),were improved.Results: Cerebrospinal fluid examination found that anti-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)2 antibody was strongly positive,although the patient had repeated gastrointestinal hemorrhage but,after hormone combined with immunoglobulin treatment,the symptoms gradual-ly improved.Conclusion:Mental disorders are not all psychosis,and autoimmune encephalitis should not be ignored.It is very important to perform anti-AMPAR encephalitis antibody test;accurate diagnosis and timely treatment can improve the prognosis.

Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats

Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage（HIBD）.However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the left common carotid artery was ligated in neonatal rats,and the rats were subjected to hypoxia for 2 hours.Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine（10 m M in 10 μL） or the autophagy stimulator rapamycin（1 g/kg） 1 hour before artery ligation.Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR 1,but by reduced expression of GluR 2.Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury,whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury.Additionally,3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of Glu R1 and downregulation of GluR2 in the hippocampus.By contrast,rapamycin further elevated hippocampal Glu R1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD.Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats,at least in part,through normalizing Glu R1 and GluR2 expression.

Genetic variables of the glutamatergic system associated with treatment-resistant depression:A review of the literature

Depression is a common,recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide.Up to 15%-40%of cases do not respond to diverse pharmacological treatments and,thus,can be defined as treatment-resistant depression(TRD).The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment.Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD.Specifically,the N-methyl-D-aspartic acid receptor(NMDAR)andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR),which are targeted by ketamine and esketamine,are proposed as promising pathways.A literature search was performed to identify studies on the genetics of the glutamatergic system in depression,focused on variables related to NMDARs and AMPARs.Our review highlights GRIN2B,which encodes the NR2B subunit of NMDAR,as a candidate gene in the pathogenesis of TRD.In addition,several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation.These genes encoding glutamatergic receptors could,therefore,be candidate genes for understanding the etiopathogenesis of TRD,as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.

α-氨基羟甲基噁唑丙酸受体与听觉神经系统

α氨基羟甲基噁唑丙酸(AMPA)受体是脊柱动物中枢神经系统一类主要的兴奋性神经递质受体,在中枢神经系统的信号传导、神经发育以及突触的可塑性等方面都起着至关重要的作用。本文阐述了AMPA受体在听觉神经系统中的分布、生物学特征及和它在听觉神经系统发育、突触传递过程中所起的作用。

Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion

Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region.The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged.Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion,but had no effect on Synapsin I levels.Besides,we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus.This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats,and suggests that these positive effects occur via the upregulation of the postsynaptic membrane a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018.

Binocular form deprivation influences the visual cortex

a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are considered to play a crucial role in synaptic plasticity in the developing visual cortex. In this study, we established a rat model of binocular form deprivation by suturing the rat binocular eyelids before eye-opening at postnatal day 14. During development, the decay time of excitatory postsynaptic currents mediated by a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptors of normal rats became longer after eye- opening; however, the decay time did not change significantly in binocular form deprivation rats. The peak value in the normal group became gradually larger with age, but there was no significant change in the binocular form deprivation group. These findings indicate that binocular form deprivation influences the properties of excitatory postsynaptic currents mediated by a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the rat visual cortex around the end of the critical period, indicating that form stimulation is associated with the experience-dependent modification of neuronal synapses in the visual cortex.

A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats

Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C(TMEM16C)/Slack is required for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor(AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively,with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia(DRG) and spinal cord.Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanilinduced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

Effects of intracerebroventricular NMDA and non-NMDA receptor agonists or antagonists on general anesthesia of propofol in mice

The effects of intracerebroventricular(icv)agonists and antagonists of N-methyl-D-aspartate(NMDA)and alpha-amino-3-hydroxy–5-methyl-4-isoxazole-propionic acid(AMPA)receptors on the general anesthesia of propofol were studied.A total of 144 Kunming mice,male and female with body mass of(22P3)g,were used.Part One of the Experiment:a total of 104 Kunming mice,male and female,were randomly divided into 13 groups.Intracerebroventricular artificial cerebral fluid(aCSF)or different doses of NMDA,AMPA,MK-801 or NBQX was injected immediately after intravenously administered propofol 25 mg/kg and the recovery time following the loss of righting reflex(LORR)was recorded.Part Two of the Experiment:a total of 40 Kunming female mice were divided randomly into 5 groups and injected with icv aCSF or NMDA,AMPA,MK-801 or NBQX after intraperitoneally administered propofol 50 mg/kg.The pain threshold of the mice was then investigated by hot-plate test(HPPT).NMDA(0.05 or 0.075μg,icv)or AMPA(0.05μg,icv)exhibited no effects on the LORR,but NMDA(0.1μg,icv)or AMPA(0.075 or 0.1μg,icv)prolonged the LORR significantly compared with the aCSF group(P<0.05,P<0.01).The LORR of the 2μg MK-801 group had no changes,while those of the 4 or 8μg MK-801 groups were prolonged significantly.The LORR of the 0.5,2 or 4μg NBQX groups were all prolonged significantly.NMDA 0.05μg or AMPA 0.05μg decreased the pain threshold slightly but did not differ in effect compared with the aCSF group;2μg MK-801 or 0.5μg NBQX both increased the pain threshold significantly.Our results indicate that propofol produces general anesthesia partly through an interaction with brain NMDA and AMPA receptors in mice.