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Allie J Widman, Lori L McMahon
Low-dose ketamine, an open-channel N -methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 2018: CNS Drugs
M Amin Khan, David R Houck, Amanda L Gross, Xiao-Lei Zhang, Cassia Cearley, Torsten M Madsen, Roger A Kroes, Patric K Stanton, Jeffrey Burgdorf, Joseph R Moskal
Background: N-methyl-D-aspartate receptors are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro-β-lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known N-methyl-D-aspartate receptor agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid, or ifenprodil...
March 1, 2018: International Journal of Neuropsychopharmacology
Qichao Wu, Yanjun Zhao, Xiangyuan Chen, Minmin Zhu, Changhong Miao
Activated microglia, involved in the occurrence and improvement of sepsis-associated encephalopathy, can induce the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, resulting in inflammation-mediated neuronal cell death. It was reported that propofol could inhibit lipopolysaccharide (LPS) induced pro-inflammatory cytokine and pro-inflammatory enzyme expression in BV2 and primary microglial cells. However, the underlying mechanism is not well known. In the present study, we investigated whether and how propofol inhibited LPS-induced the expression of pro-inflammatory cytokines and pro-inflammatory enzymes in BV2 cells...
March 2018: Canadian Journal of Physiology and Pharmacology
Andrei-Nicolae Vasilescu, Nina Schweinfurth, Stefan Borgwardt, Peter Gass, Undine E Lang, Dragos Inta, Sarah Eckart
Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine...
2017: Neuropsychiatric Disease and Treatment
Qichao Wu, Yanjun Zhao, Wenming Duan, Yi Liu, Xiangyuan Chen, Minmin Zhu
Perioperative hyperglycemia is a common clinical metabolic disorder. Hyperglycemia could induce endothelial apoptosis, dysfunction and inflammation, resulting in endothelial injury. Propofol is a widely used anesthetic drug in clinical settings. Our previous studies indicated that propofol, via inhibiting high glucose-induced phosphatase A2 (PP2A) expression, attenuated high glucose-induced reactive oxygen species (ROS) accumulation, thus improving endothelial apoptosis, dysfunction and inflammation. However, the mechanisms by which propofol attenuated high glucose-induced PP2A expression is still obscure...
April 2017: Vascular Pharmacology
Ricardo P Garay, Carlos A Zarate, Thomas Charpeaud, Leslie Citrome, Christoph U Correll, Ahcène Hameg, Pierre-Michel Llorca
The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future. Areas covered: Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week...
June 2017: Expert Review of Neurotherapeutics
Xiangyuan Chen, Qichao Wu, Li You, Sisi Chen, Minmin Zhu, Changhong Miao
Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1α (HIF-1α) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF-1α expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells...
January 15, 2017: European Journal of Pharmacology
Ashish Dhir
Treatment of patients suffering from major depression could be highly challenging for psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to functional impairment and poor quality of life. The present review discusses some of the novel investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression. Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of major depression are covered in this article...
January 2017: Expert Opinion on Investigational Drugs
Carolyn I Rodriguez, Jordana Zwerling, Eyal Kalanthroff, Hanyang Shen, Maria Filippou, Booil Jo, Helen Blair Simpson, Ronald M Burch, Joseph R Moskal
No abstract text is available yet for this article.
December 1, 2016: American Journal of Psychiatry
Bangkun Yang, Ji-Chun Zhang, Mei Han, Wei Yao, Chun Yang, Qian Ren, Min Ma, Qian-Xue Chen, Kenji Hashimoto
RATIONALE: The N-methyl-D-aspartate (NMDA) receptor antagonists, including R-ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression. OBJECTIVE: We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model. RESULTS: In the tail suspension and forced swimming tests, R-ketamine (10 mg/kg, intraperitoneal (i.p.)) or rapastinel (10 mg/kg, i...
October 2016: Psychopharmacology
Joseph R Moskal, Jeffrey S Burgdorf, Patric K Stanton, Roger A Kroes, John F Disterhoft, Ronald M Burch, M Amin Khan
BACKGROUND: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. METHODS: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21...
2017: Current Neuropharmacology
Jaak Panksepp
Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong-to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states...
December 2015: Dialogues in Clinical Neuroscience
Megan M Eaton, Allison L Germann, Ruby Arora, Lily Q Cao, Xiaoyi Gao, Daniel J Shin, Albert Wu, David C Chiara, Jonathan B Cohen, Joe Henry Steinbach, Alex S Evers, Gustav Akk
BACKGROUND: Propofol is a sedative agent that at clinical concentrations acts by allosterically activating or potentiating the γ-aminobutyric acid type A (GABAA) receptor. Mutational, modeling, and photolabeling studies with propofol and its analogues have identified potential interaction sites in the transmembrane domain of the receptor. At the "+" of the β subunit, in the β-α interface, meta-azipropofol labels the M286 residue in the third transmembrane domain...
2016: Current Neuropharmacology
Lakshmi Rajagopal, Jeffrey S Burgdorf, Joseph R Moskal, Herbert Y Meltzer
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited...
February 15, 2016: Behavioural Brain Research
H Javelot
Pharmacological treatment of acute anxiety still relies on benzodiazepines, while chronic anxiety disorders and depression are treated with different antidepressants, according to specific indications. The monoaminergic axis is represented by two families which are being developed: (i) serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRI), also called triple reuptake inhibitors (TRI), for the treatment of depression (amitifadine), (ii) multimodal antidepressants for depression and anxiety disorders (generalized anxiety disorder mainly) (tedatioxetine, vortioxetine and vilazodone)...
March 2016: Annales Pharmaceutiques Françaises
D Jeffrey Newport, Linda L Carpenter, William M McDonald, James B Potash, Mauricio Tohen, Charles B Nemeroff
OBJECTIVE: The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. METHOD: Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects...
October 2015: American Journal of Psychiatry
J Burgdorf, X-L Zhang, C Weiss, A Gross, S R Boikess, R A Kroes, M A Khan, R M Burch, C S Rex, J F Disterhoft, P K Stanton, J R Moskal
Rapastinel (GLYX-13) is an N-methyl-d-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays...
November 12, 2015: Neuroscience
Jeffrey Burgdorf, Roger A Kroes, Xiao-lei Zhang, Amanda L Gross, Mary Schmidt, Craig Weiss, John F Disterhoft, Ronald M Burch, Patric K Stanton, Joseph R Moskal
Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Contextual fear extinction (CFE) in rodents has been well characterized and used extensively as a model to study the neurobiological mechanisms of post-traumatic stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, studies were undertaken to examine the effects of rapastinel for its therapeutic potential in PTSD and to use rapastinel as a tool to study its underlying glutamatergic mechanisms...
November 1, 2015: Behavioural Brain Research
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