RESUMEN
The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. In vivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.
Asunto(s)
Anticonvulsivantes , Fenitoína , Humanos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Fenitoína/uso terapéutico , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Convulsiones/prevención & control , Piridinas/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia mongolica is well known for its use in folk medicine, it is commonly used to alleviate a variety of diseases associated with inflammation, such as laryngitis, tonsillitis, headaches and hepatitis in northwest China. However, its anti-inflammatory mechanism is still unknown. AIM OF THE STUDY: The most potential anti-inflammatory part (AMPA) was identified by screening individual parts of A. Mongolica. After the network pharmacological analysis, the anti-inflammation effects and molecular mechanisms of AMPA were evaluated in RAW264.7 cells induced by LPS. MATERIALS AND METHODS: AMPA was chosen as the most anti-inflammatory of the A. Mongolica, as measured by the effect of each part of the A. Mongolica on NO and COX-2. The chemical composition of AMPA was identified using HPLC-Q-TOF-MS/MS, and targets of bioactive chemicals and targets related to inflammation were found using open-source databases. The "Compound-targets" network and PPI network were established by combining compounds and overlapped targets, and targets in the PPI networks were analyzed by GO and KEGG enrichment. The RAW26.7 cells induced by LPS were used as a model of inflammation examination. MTT assay was performed to assess the cytotoxicity of AMPA on LPS-induced RAW264.7 cells. The level of NO was measured by the Griess method while the inflammatory factors were detected by ELISA. The protein expression levels of iNOS, COX-2, MAPK, NF-κB signaling pathway and AMPK/Nrf2-related proteins were determined by Western blot. The results of nuclear translocation of p65 and Nrf2 were analyzed by immunofluorescence assay. RESULTS: A total of 18 compounds with potential bioactivity were identified, and after intersecting 640 compound-predicted targets and 1608 inflammation targets, the compounds and intersected targets were utilized to structure "compound-target" and PPI networks. Among AMPA, AM6, AM7, AM11, AM8 and AM1 compounds were essential in the "compound-targets" network, meanwhile, TNF, RELA, MAPK1, NOS2, PRKAG, and PTGS2 targets play important roles in the PPI network. The top 10 terms and pathways were obtained based on GO and KEGG. The cell experiments show that 50 µg/mL was the maximum concentration of AMPA without cytotoxicity in the LPS-induced RAW264.7 cell model. When compared with the LPS group, AMPA treatment not only effectively suppressed the generation of NO, TNF-α, IL-6, PGE2, IL-1ß and MCP-1 in LPS-induced RAW264.7 cells, but also down-regulated the expression of COX-2, iNOS and the protein levels p-ERK, p-p38, p-IκB-α and p-p65, inhibited the nuclear translocation of p65. Furthermore, the expression levels of p-LKB1, p-AMPK, Nrf2 and HO-1 proteins were up-regulated and Nrf2 nuclear translocation was promoted. CONCLUSION: AMPA should be considered an anti-inflammatory agent for the results of network pharmacology and in vitro, which could inhibit the MAPK pathway and NF-κB pathway and activate the AMPK/Nrf2 pathway in LPS-stimulated RAW264.7 cells.
Asunto(s)
Artemisia , FN-kappa B , Animales , Ratones , FN-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Ciclooxigenasa 2 , Proteínas Quinasas Activadas por AMP , Farmacología en Red , Espectrometría de Masas en Tándem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Células RAW 264.7 , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND: Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse events (AEs) for ASMs and other coadministered drugs (CDs) is essential for practitioners and patients. Due to frequent polypharmacy, it is often difficult to clinically assess the AE profiles of ASMs and differentiate the influence of CDs. OBJECTIVE: This retrospective analysis aimed to determine typical AE profiles for ASMs and assess the impact of CDs on AEs in clinical practice. METHODS: The Liverpool AE Profile (LAEP) and its domains were used to identify the AE profiles of ASMs based on data from a large German multicenter study (Epi2020). Following established classifications, drugs were grouped according to their mode of action (ASMs) or clinical indication (CDs). Bivariate correlation, multivariate ordinal regression (MORA), and artificial neural network (ANNA) analyses were performed. Bivariate correlation with Fisher's z-transformation was used to compare the correlation strength of LAEP with the Hospital Anxiety and Depression Scale (HADS) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to avoid LAEP bias in the context of antidepressant therapy. RESULTS: Data from 486 patients were analyzed. The AE profiles of ASM categories and single ASMs matched those reported in the literature. Synaptic vesicle glycoprotein 2A (SV2A) and voltage-gated sodium channel (VGSC) modulators had favorable AE profiles, while brivaracetam was superior to levetiracetam regarding psychobehavioral AEs. MORA revealed that, in addition to seizure frequency, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators and antidepressants were the only independent predictors of high LAEP values. After Fisher's z-transformation, correlations were significantly lower between LAEP and antidepressants than between LAEP and HADS or NDDI-E. Therefore, a bias in the results toward over interpreting the impact of antidepressants on LAEP was presumed. In the ANNA, perampanel, zonisamide, topiramate, and valproic acid were important nodes in the network, while VGSC and SV2A modulators had low relevance for predicting relevant AEs. Similarly, cardiovascular agents, analgesics, and antipsychotics were important CDs in the ANNA model. CONCLUSION: ASMs have characteristic AE profiles that are highly reproducible and must be considered in therapeutic decision-making. Therapy using perampanel as an AMPA modulator should be considered cautiously due to its relatively high AE profile. Drugs acting via VGSCs and SV2A receptors are significantly better tolerated than other ASM categories or substances (e.g., topiramate, zonisamide, and valproate). Switching to brivaracetam is advisable in patients with psychobehavioral AEs who take levetiracetam. Because CDs frequently pharmacokinetically interact with ASMs, the cumulative AE profile must be considered. TRIAL REGISTRATION: DRKS00022024, U1111-1252-5331.
Asunto(s)
Anticonvulsivantes , Epilepsia , Adulto , Humanos , Anticonvulsivantes/efectos adversos , Levetiracetam/uso terapéutico , Topiramato , Zonisamida , Estudios Retrospectivos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Epilepsia/tratamiento farmacológico , Ácido Valproico/uso terapéuticoRESUMEN
The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and activating them in the sub-acute phase on post-stroke recovery in middle cerebral artery occlusion (MCAo) model of stroke in rats. After 90 min of MCAo, perampanel (an AMPAR antagonist, 1.5 mg/kg i.p) and aniracetam (an AMPA agonist, 50 mg/kg i.p.) were administered for different durations after MCAo. Later, after obtaining the best time point for the antagonist and the agonist treatment protocols, sequential treatment with perampanel and aniracetam were given, and the effect on neurological damage and post stroke recovery were assessed. Perampanel and aniracetam significantly protected MCAo-induced neurological damage and diminished the infarct percentage. Furthermore, treatment with these study drugs improved the motor coordination and grip strength. Sequential treatment with perampanel and aniracetam reduced the infarct percentage as assessed by MRI. Moreover, these compounds diminished the inflammation via reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1ß) and increasing the levels of anti-inflammatory cytokine (IL-10) along with reductions in GFAP expression. Moreover, the neuroprotective markers (BDNF and TrkB) were found to be significantly increased. Levels of apoptotic markers (Bax, cleaved-caspase-3; Bcl2 and TUNEL positive cells) and neuronal damage (MAP-2) were normalized with the AMPA antagonist and agonist treatment. Expressions of GluR1 and GluR2 subunits of AMPAR were significantly enhanced with sequential treatment. The present study thus showed that modulation of AMPAR improves neurobehavioral deficits and reduces the infarct percentage through anti-inflammatory, neuroprotective and anti-apoptotic effects.
Asunto(s)
Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Accidente Cerebrovascular , Ratas , Animales , Receptores AMPA/metabolismo , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Modelos Teóricos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
As a neurodegenerative disease, Alzheimer's disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aß plaques. Histone deacetylase (HDAC) mediates the damage of Aß oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 µM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aß deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.
Asunto(s)
Enfermedad de Alzheimer , Neuroblastoma , Enfermedades Neurodegenerativas , Proteínas Adaptadoras Transductoras de Señales , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Proteínas Portadoras , Modelos Animales de Enfermedad , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Receptores AMPA/genética , Receptores AMPA/metabolismo , Receptores AMPA/uso terapéutico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune inflammatory disease predominantly found in women of child-bearing age. Neurogenic pulmonary edema (NPE) is a recalcitrant complication that occurs after injury to the central nervous system and has an acute onset and rapid progression. Limbic encephalitis is an inflammatory encephalopathy caused by viruses, immune responses, or other factors involving the limbic system. NPE caused by SLE is rare. CASE PRESENTATION: Here, we report a case of a 21-year-old woman with SLE who experienced five episodes of generalized tonic-clonic seizure after headache and dyspnea. Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 2 antibody was tested positive in the serum and cerebrospinal fluid. Electrocardiography (EEG) indicated paroxysmal or sporadic medium amplitude theta activity. In addition, chest computed tomography (CT) showed multiple diffuse consolidations and ground-glass opacities. We finally considered a diagnosis of NPE and AMPAR limbic encephalitis. The patient's symptoms improved obviously after methylprednisolone pulse therapy and antiepileptic treatment. CONCLUSIONS: NPE can be a complication of neuropsychiatric lupus erythematosus (NPSLE). AMPAR2 antibodies may be produced in NPSLE patients, especially in those with high polyclonal IgG antibody titers. More basic and clinical studies are required to confirm these observations and elucidate the pathogenicity of encephalitis-related autoantibodies in SLE patients.
Asunto(s)
Encefalitis Límbica , Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Edema Pulmonar , Adulto , Autoanticuerpos , Femenino , Humanos , Encefalitis Límbica/complicaciones , Encefalitis Límbica/diagnóstico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Edema Pulmonar/complicaciones , Adulto Joven , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) is thought to cause acute brain injury, but the role remains poorly understood in subarachnoid hemorrhage (SAH). This study was conducted to evaluate if AMPAR activation induces acute blood-brain barrier (BBB) disruption after SAH. C57BL/6 male adult mice (n = 117) underwent sham or filament perforation SAH modeling, followed by a random intraperitoneal injection of vehicle or two dosages (1 mg/kg or 3 mg/kg) of a selective noncompetitive AMPAR antagonist perampanel (PER) at 30 min post-modeling. The effects were evaluated by mortality, neurological scores, and brain water content at 24-48 h and video electroencephalogram monitoring, immunostaining, and Western blotting at 24 h post-SAH. PER significantly suppressed post-SAH neurological impairments, brain edema, and BBB disruption. SAH developed epileptiform spikes without obvious convulsion, which were also inhibited by PER. Western blotting showed that the expression of AMPAR subunits GluA1 and GluA2 was unchanged after SAH, but they were significantly activated after SAH. PER prevented post-SAH activation of GluA1/2, associated with the suppression of post-SAH induction of tenascin-C, a causative mediator of post-SAH BBB disruption. Meanwhile, an intracerebroventricular injection of a subtype-selective GluA1/2 agonist augmented the activation of GluA1/2 and the induction of tenascin-C in brain capillary endothelial cells and aggravated post-SAH BBB disruption without increases in epileptiform spikes. Neurological impairments and brain edema were not correlated with the occurrence of epileptiform spikes. This study first showed that AMPAR plays an important role in the development of post-SAH BBB disruption and can be a novel therapeutic target against it.
Asunto(s)
Edema Encefálico , Hemorragia Subaracnoidea , Animales , Barrera Hematoencefálica/metabolismo , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Células Endoteliales/metabolismo , Femenino , Isoxazoles/metabolismo , Isoxazoles/farmacología , Isoxazoles/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Propionatos/metabolismo , Propionatos/farmacología , Propionatos/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Tenascina/metabolismo , Tenascina/farmacología , Tenascina/uso terapéutico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
Background: Primary orthostatic tremor (POT) remains a therapeutic conundrum. Various medication classes have been tried, yielding modest results at best. Case Report: A 62-year-old female with a 13-year history of POT, refractory to clonazepam up to 20 mg/day, was treated with perampanel 1-2 mg/day. She reported 90% subjective symptomatic improvement. Discussion: This case highlights the potential for use of perampanel, a novel AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist for the treatment of POT. There has been one prior report citing its use for POT with complete resolution of symptoms. We encourage further studies to highlight its efficacy for POT.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Mareo/tratamiento farmacológico , Piridonas/uso terapéutico , Temblor/tratamiento farmacológico , Clonazepam/uso terapéutico , Mareo/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Nitrilos , Receptores AMPA/efectos de los fármacos , Resultado del Tratamiento , Temblor/diagnóstico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
Neurotrauma results in the progressive degeneration of neurons and glia surrounding the initial injury. Disruptions to myelin structure are a feature of these injuries and are thought to be triggered by excess calcium (Ca2+) influx into myelinating oligodendrocytes and/or their precursor cells. Calcium ions enter oligodendrocytes through a range of receptors including voltage gated calcium channels, N-methyl-D-aspartate (NMDA) receptors, Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and purinergic P2X7 receptors. Inhibitors have been used to limit excess Ca2+ entry following neurotrauma, but clinical success has been limited. We propose that combinations of calcium channel inhibitors may provide an alternative treatment strategy, whereby entry of excess Ca2+ flux through multiple routes is inhibited simultaneously.
Asunto(s)
Lesiones Encefálicas/tratamiento farmacológico , Calcio/metabolismo , Canales Iónicos/antagonistas & inhibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Lesiones Encefálicas/metabolismo , HumanosRESUMEN
Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Receptores AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/análogos & derivados , Adulto , Regulación Alostérica , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hormona de Crecimiento Humana/metabolismo , Humanos , Hidrocortisona/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/efectos adversos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
BACKGROUND: It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing. METHODS: Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100-300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100-300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology. RESULTS: Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100-300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache. CONCLUSIONS: These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Atención/efectos de los fármacos , Receptores AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/análogos & derivados , Adulto , Animales , Estudios Cruzados , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/efectos adversos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
Previous work demonstrated that basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activity did not contribute to the elevated regional cerebral O2 consumption in the brains of Eker rat (an autism-tuberous sclerosis model). We tested the hypothesis that increased stimulation of AMPA receptors also would not augment cerebral O2 consumption in the Eker rat. Three cortical sites were prepared for administration of saline, 10â»4 and 10⻳ M AMPA in young (4 weeks) male control Long Evans and Eker rats (70-100 g). Cerebral blood flow (¹4C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. Receptor levels were studied through Western analysis of the GLuR1 subunit of the AMPA receptor. We found significantly increased cortical O2 consumption (+33%) after 10â»4 M AMPA in control rats. The higher dose of AMPA did not further increase consumption. In the Eker rats, neither dose led to a significant increase in cortical O2 consumption. Regional blood flow followed a similar pattern to oxygen consumption but cortical O2 extraction did not differ. Cortical AMPA receptor protein levels were significantly reduced (-21%) in the Eker compared to control rats. Both O2 consumption and blood flow were significantly elevated in the pons of the Eker rats compared to control. These data demonstrate a reduced importance of AMPA receptors in the control of cortical metabolism, related to reduced AMPA receptor protein, in the Eker rat. This suggests that increasing AMPA receptor activity may not be an effective treatment for children with autism spectrum disorders as they also have reduced AMPA receptor number.
Asunto(s)
Trastorno Autístico/tratamiento farmacológico , Corteza Cerebral/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Consumo de Oxígeno/efectos de los fármacos , Receptores AMPA/agonistas , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Animales , Trastorno Autístico/metabolismo , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Circulación Cerebrovascular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Masculino , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Puente/irrigación sanguínea , Puente/efectos de los fármacos , Puente/crecimiento & desarrollo , Puente/metabolismo , Subunidades de Proteína/agonistas , Subunidades de Proteína/metabolismo , Ratas , Ratas Long-Evans , Ratas Mutantes , Receptores AMPA/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificaciónRESUMEN
Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/uso terapéutico , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Humanos , Ketamina/administración & dosificación , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Índice de Severidad de la Enfermedad , Factores de Tiempo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoRESUMEN
We have previously reported that topical application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to the rat neocortex prevents the effects of a subsequent application of N-methyl-d-aspartic acid (NMDA). Activation of NMDA receptors is involved in the pathogenesis of epileptic activity. Therefore, we examined if topically applied AMPA could affect changes in the somatosensory evoked potentials (SEPs) and electrocorticogram (ECoG) epileptic spikes caused by bicuculline. AMPA (50 microM) prevented the epileptiform activity to a level that was comparable to that caused by diazepam (3 mg/kg i.p.) or clomethiazole (100 mg/kg i.p.). Also, the epileptiform activity was suppressed by the AMPAR antagonist, CNQX, or the blocker of AMPAR desensitization, cyclothiazide. In the hippocampal slice, bicuculline-induced changes in the population spike potentials recorded from the CA1 cells were not affected by AMPA. We conclude that in the complex neuronal network of the rat neocortex, epileptiform activity can be suppressed in a variety of strategies that target the AMPA receptors: (1) blocking AMPA receptors, (2) promoting an apparent desensitization of AMPA receptors (possibly on the pyramidal neurons) or (3) reducing an apparent desensitization of AMPA receptors (possibly on the inhibitory GABA-ergic interneurons).
Asunto(s)
Epilepsia/fisiopatología , Neocórtex/fisiopatología , Receptores AMPA/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Benzotiadiazinas/farmacología , Bicuculina , Clormetiazol/farmacología , Clormetiazol/uso terapéutico , Diazepam/farmacología , Diazepam/uso terapéutico , Electroencefalografía/métodos , Epilepsia/inducido químicamente , Epilepsia/prevención & control , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Potenciales Evocados Somatosensoriales/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/citología , Técnicas In Vitro , Masculino , Neocórtex/efectos de los fármacos , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéuticoAsunto(s)
Deficiencia de Magnesio/complicaciones , Quinoxalinas/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/prevención & control , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/uso terapéutico , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Convulsiones/etiologíaRESUMEN
Intracerebroventricular (i.c.v.) infusion in mice of the selective metabotropic excitatory amino acid receptor agonist 1S,3R-1- aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (0.6-575 nmol/min) dose dependently induced face washing and scratching. In contrast, the subtype-specific ionotropic excitatory amino acid receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (0.3-3.0 nmol/min) dose dependently induced clonic convulsions. I.c.v. infusion of the non-selective metabotropic receptor agonists ibotenate (6 nmol/min) or quisqualate (30 nmol/min) induced clonic convulsions. However, when ionotropic receptors were blocked with (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801, dizoclipine) (3 nmol/min) or 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(f)-quinoxaline (NBQX) (9 nmol/min), respectively, face washing and scratching behavior emerged. Neither MK-801 or NBQX (ED50 value > 100 nmol/min), nor the putative metabotropic receptor antagonist L-amino-3-phosphoro-propionic acid (L-AP3) (> 176 nmol/min); nor the dopamine receptor antagonists SCH 23390 (> 74 nmol/min), metoclopramide (> 89 nmol/min) and haloperidol (> 27 nmol/min) antagonized 1S,3R-ACPD-induced scratching (144 nmol/min). These results suggest that the behavioral consequences of i.c.v. infusion of 1S,3R-ACPD in mice reflect a selective activation of metabotropic receptors that differs from the behavioral changes observed with i.c.v. infusion of ionotropic receptor agonists.