Charles F. Zorumski

Bio: Charles F. Zorumski is an academic researcher from Washington University in St. Louis. The author has contributed to research in topics: Long-term potentiation & NMDA receptor. The author has an hindex of 69, co-authored 311 publications receiving 16966 citations. Previous affiliations of Charles F. Zorumski include Baylor College of Medicine & University of Nebraska Medical Center.

Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits

Abstract: Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABAA receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABAA receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin

Abstract: Extensive research has failed to clarify the mechanism of action of nitrous oxide (N2O, laughing gas), a widely used inhalational anesthetic and drug of abuse. Other general anesthetics are thought to act by one of two mechanisms-blockade of NMDA glutamate receptors or enhancement of GABAergic inhibition. Here we show that N2O, at anesthetically-relevant concentrations, inhibits both ionic currents and excitotoxic neurodegeneration mediated through NMDA receptors and, like other NMDA antagonists, produces neurotoxic side effects which can be prevented by drugs that enhance GABAergic inhibition. The favorable safety record of N2O may be explained by the low concentrations typically used and by the fact that it is usually used in combination with GABAergic anesthetics that counteract its neurotoxic potential.

Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial.

Abstract: Importance Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production. Objective To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease. Design, Setting, and Participants Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020. Interventions Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days. Main Outcomes and Measures The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Results Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rankP = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. Conclusions and Relevance In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures. Trial Registration ClinicalTrials.gov Identifier:NCT04342663

Glial contributions to excitatory neurotransmission in cultured hippocampal cells

Abstract: Although many glial cells possess neurotransmitter receptors and transporters, little is known about glial participation in neurotransmission. To explore this issue, we recorded neuronal autaptic and glial responses from cultured hippocampal single-neuron micro-islands. Excitatory synaptic events activate rapid electrogenic glial glutamate transporter currents similar to those elicited by exogenous glutamate in other preparations. We show here that glial transporter responses may be used to sense changes in presynaptic efficacy and that glial uptake helps to remove synaptically released glutamate, thereby contributing to the termination of excitatory synaptic currents under certain conditions. These observations provide a framework for understanding the role of glia in both normal and pathological processes.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

A synaptic model of memory: long-term potentiation in the hippocampus

Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

Short-Term Synaptic Plasticity

Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

The glutamate receptor ion channels

Abstract: The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this