DOCSLIB.ORG

(NMDA) Receptor Encephalitis Is an Autoimmune Seizures and Autonomic Dysfunction

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(NMDA) Receptor Encephalitis Is an Autoimmune Seizures and Autonomic Dysfunction Nonprofit Organization U.S. Postage PAID Twin Cities, MN VOLUME 23, NUMBER 4 200 University Ave. E. Permit No. 5388 St. Paul, MN 55101 651-291-2848 ADDRESSwww.gillettechildrens.org SERVICE REQUESTED VOLUME 23, NUMBER 4 2014 A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA receptor encephalitis Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune seizures and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have epilepsy and other neurological conditions. as one of the most common identifiable causes of encephalitis in children and She received an M.D. from the University of Iowa’s Carver ■ Time-to-diagnosis and treatment of young adults. College of Medicine in Iowa City, Iowa, and completed a NEWS & NOTES anti-NMDA receptor encephalitis pediatric residency and a child neurology residency at have a significant impact on patient The Children’s Hospital Colorado in Denver. Her profes- In the California Encephalitis Project, only 79 of 761 cases of encephalitis in recovery and final outcome. individuals under age 30 had an identifiable etiology. Anti-NMDA receptor sional interests include anti-NMDA receptor encephalitis, New Physician Joins Gillette neuroimmunology, leukodystrophies and other metabolic Visit www.gillettechildrens.org/ encephalitis accounted for 32 of those cases, and 65 percent of those patients Joy Taber, M.D., is board-certified in physical medicine and rehabilitation. She cares for and genetic neurological disorders. OurCareTeam to learn more about were younger than 19. Additionally, the study showed that anti-NMDA receptor Gillette’s specialists. adult patients who have cerebral palsy, spina bifida and other childhood-onset conditions. She received a medical degree and completed her residency in physical medicine and encephalitis may be more common than any single infectious cause of encephalitis, Clinical Education rehabilitation at the University of Minnesota School of Medicine in Minneapolis. In other than enterovirus.1 Visit our website to find videos and addition, she served as a U.S. Air Force flight surgeon. She is a member of the American professional presentations. Academy of Physical Medicine and Rehabilitation, American Medical Association and www.gillettechildrens.org Minnesota Medical Association. She sees patients at Gillette Lifetime Specialty Healthcare. Frequency of Identifiable Causes of Encephalitis in the California Encephalitis Project Back Issues of A Pediatric Perspective www.gillettechildrens.org/for-medical- professionals/publications Anti-NMDA receptor encephalitis Gillette Children’s Specialty Healthcare Enterovirus is named in honor of orthopedic surgeon Herpes Simplex Virus (HSV-1) Arthur Gillette, M.D., who helped found West Nile Virus the nation’s first publicly funded hospital for children who have disabilities. We are Varicella Zoster Virus an independent, not-for-profit children’s hospital, and our organization has no affiliation with the Gillette Company or the Gillette brand of personal care products. www.gillettechildrens.org Clinical Presentation Autonomic Dysfunction • Occasionally, brain MRIs will show white matter lesions with • Other medications are often needed to treat specific Patients with anti-NMDA receptor encephalitis have a constel- • The most frequent autonomic manifestations include associated enhancement after contrast that is consistent with symptoms, such as seizures, abnormal movements lation of symptoms that are recognizable to providers familiar fever, tachycardia, hypertension, bradycardia and demyelination. Patients with demyelinating lesions and confirmed or psychosis. with the condition. However, comparisons of presentations hypersalivation. anti-NMDA receptor encephalitis should be tested for anti-NMO • Rehabilitation programs, with intensive physical, among patients with this condition show significant variability. • A small percentage of patients develop hypoventi- antibodies, which have been found in this subset of patients. occupational and speech therapy, are important to lation, even when consciousness is preserved, and help patients regain function, and an inpatient Most patients will exhibit multiple, but not all, possible symptoms Young Child With Anti-NMDA Receptor of the condition. The order in which symptoms develop can vary require respiratory support. Electroencephalogram (EEG) admission to a specialized rehabilitation unit is • Close monitoring of vital signs is recommended for • EEGs are used to assess the background activity and to evaluate often required. Encephalitis from patient to patient, and not all symptoms may be present all patients. for seizures. during the initial evaluation. Additionally, presentation varies History: The mother of a 4-year-old girl brought her daughter • Most patients with anti-NMDA receptor encephalitis will have by age group. Very young children present with symptoms that Outcomes to the emergency room because of a change in behavior. are distinct from those seen in teens and adults. Differential Diagnosis an abnormal EEG at some point in their disease course. At least 75 percent of patients will have substantial She reported that the girl had seemed sad and unlike herself The differential diagnosis of anti-NMDA receptor • 90 percent of patients will have slowing of background frequencies. recovery. The rate and degree of recovery appear to be for one week. She first noticed her daughter having frequent Psychiatric Symptoms encephalitis is broad and includes infectious causes • 25 to 50 percent will have epileptic features, such as spike and related to how quickly a diagnosis is made and treat- episodes of crying for no apparent reason. During the preceding week, the girl also seemed more tired than normal, and she • The most common presenting symptoms in teenagers and of encephalitis, such as herpes simplex virus; acute wave discharges or captured seizures. ment is begun using appropriate immunomodulating had low grade fevers to 100.1 F. Four days earlier, her mother adults include anxiety, insomnia, delusions, mania and paranoia. disseminated encephalomyelitis (ADEM); inborn errors agents. There is limited information about cognitive Infectious Disease Evaluation observed that her daughter seemed to be constantly playing • Young children tend to present with behavior changes, temper of metabolism, including urea cycle disorders; environ- and psychological outcomes in these patients; how- with her tongue, chewing on it and running it over her teeth. • The evaluation for viral encephalitis is individualized, tantrums, hyperactivity and irritability, instead of overt mental toxins and medication overdoses; rheumatologic ever, my experience suggests that these problems are She also noticed that the girl seemed to be fidgeting with her and depends on time of year and geographic location. psychotic symptoms. conditions, such as neuropsychiatric lupus; and primary under-recognized in patients with otherwise excellent hands more, “like she was anxious and couldn’t keep them • Every patient should be tested for herpes simplex virus (HSV). • This initial phase is often followed by a stage with periods of psychiatric conditions, such as schizophrenia. Due to neurologic recovery. still.” The patient was seen by her pediatrician and a psych- • The infectious disease team is often consulted to co-evaluate alternating agitation and catatonia. the extensive differential diagnosis, the diagnostic work- ologist and they felt she was depressed. Over the next two the patient. days, she stopped speaking, began sleeping very little and • Often the first provider to see the patient is a psychologist up of each patient must be individualized based on the Conclusion developed an unsteady gait. Shortly after admission to the or psychiatrist. presentation, and consultation with a child neurologist Anti-NMDA receptor encephalitis is a relatively Tumor Evaluation hospital, she had a new spell that consisted of stiffening her is recommended. common and treatable cause of encephalitis in right arm and staring. • The first cases of anti-NMDA receptor encephalitis were Language Changes pediatric patients. Any child presenting with • A reduction in spontaneous
Load more

Recommended publications
  • A Guide to Glutamate Receptors
    A guide to glutamate receptors 1 Contents Glutamate receptors . 4 Ionotropic glutamate receptors . 4 - Structure ........................................................................................................... 4 - Function ............................................................................................................ 5 - AMPA receptors ................................................................................................. 6 - NMDA receptors ................................................................................................. 6 - Kainate receptors ............................................................................................... 6 Metabotropic glutamate receptors . 8 - Structure ........................................................................................................... 8 - Function ............................................................................................................ 9 - Group I: mGlu1 and mGlu5. .9 - Group II: mGlu2 and mGlu3 ................................................................................. 10 - Group III: mGlu4, mGlu6, mGlu7 and mGlu8 ............................................................ 10 Protocols and webinars . 11 - Protocols ......................................................................................................... 11 - Webinars ......................................................................................................... 12 References and further reading . 13 Excitatory synapse pathway
    [Show full text]
  • From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J
    REVIEW The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J. David Jentsch, Ph.D., and Robert H. Roth, Ph.D. Administration of noncompetitive NMDA/glutamate effects of these drugs are discussed, especially with regard to receptor antagonists, such as phencyclidine (PCP) and differing profiles following single-dose and long-term ketamine, to humans induces a broad range of exposure. The neurochemical effects of NMDA receptor schizophrenic-like symptomatology, findings that have antagonist administration are argued to support a contributed to a hypoglutamatergic hypothesis of neurobiological hypothesis of schizophrenia, which includes schizophrenia. Moreover, a history of experimental pathophysiology within several neurotransmitter systems, investigations of the effects of these drugs in animals manifested in behavioral pathology. Future directions for suggests that NMDA receptor antagonists may model some the application of NMDA receptor antagonist models of behavioral symptoms of schizophrenia in nonhuman schizophrenia to preclinical and pathophysiological research subjects. In this review, the usefulness of PCP are offered. [Neuropsychopharmacology 20:201–225, administration as a potential animal model of schizophrenia 1999] © 1999 American College of is considered. To support the contention that NMDA Neuropsychopharmacology. Published by Elsevier receptor antagonist administration represents a viable Science Inc. model of schizophrenia, the behavioral and neurobiological KEY WORDS: Ketamine; Phencyclidine; Psychotomimetic; widely from the administration of purportedly psychot- Memory; Catecholamine; Schizophrenia; Prefrontal cortex; omimetic drugs (Snyder 1988; Javitt and Zukin 1991; Cognition; Dopamine; Glutamate Jentsch et al. 1998a), to perinatal insults (Lipska et al. Biological psychiatric research has seen the develop- 1993; El-Khodor and Boksa 1997; Moore and Grace ment of many putative animal models of schizophrenia.
    [Show full text]
  • Neurochemical Mechanisms Underlying Alcohol Withdrawal
    Neurochemical Mechanisms Underlying Alcohol Withdrawal John Littleton, MD, Ph.D. More than 50 years ago, C.K. Himmelsbach first suggested that physiological mechanisms responsible for maintaining a stable state of equilibrium (i.e., homeostasis) in the patient’s body and brain are responsible for drug tolerance and the drug withdrawal syndrome. In the latter case, he suggested that the absence of the drug leaves these same homeostatic mechanisms exposed, leading to the withdrawal syndrome. This theory provides the framework for a majority of neurochemical investigations of the adaptations that occur in alcohol dependence and how these adaptations may precipitate withdrawal. This article examines the Himmelsbach theory and its application to alcohol withdrawal; reviews the animal models being used to study withdrawal; and looks at the postulated neuroadaptations in three systems—the gamma-aminobutyric acid (GABA) neurotransmitter system, the glutamate neurotransmitter system, and the calcium channel system that regulates various processes inside neurons. The role of these neuroadaptations in withdrawal and the clinical implications of this research also are considered. KEY WORDS: AOD withdrawal syndrome; neurochemistry; biochemical mechanism; AOD tolerance; brain; homeostasis; biological AOD dependence; biological AOD use; disorder theory; biological adaptation; animal model; GABA receptors; glutamate receptors; calcium channel; proteins; detoxification; brain damage; disease severity; AODD (alcohol and other drug dependence) relapse; literature review uring the past 25 years research- science models used to study with- of the reasons why advances in basic ers have made rapid progress drawal neurochemistry as well as a research have not yet been translated Din understanding the chemi- reluctance on the part of clinicians to into therapeutic gains and suggests cal activities that occur in the nervous consider new treatments.
    [Show full text]
  • Functional Kainate-Selective Glutamate Receptors in Cultured Hippocampal Neurons (Excitatory Amino Acid Receptors/Hippocampus) JUAN LERMA*, ANA V
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11688-11692, December 1993 Neurobiology Functional kainate-selective glutamate receptors in cultured hippocampal neurons (excitatory amino acid receptors/hippocampus) JUAN LERMA*, ANA V. PATERNAIN, JosE R. NARANJO, AND BRITT MELLSTR6M Departamento de Plasticidad Neural, Instituto Cajal, Consejo Superior de Investigaciones Cientfficas, Avenida Doctor Arce 37, 28002-Madrid, Spain Communicated by Michael V. L. Bennett, September 15, 1993 ABSTRACT Glutamate mediates fast synaptic transmis- experiments, the regional distribution of high-affinity sion at the majority of excitatory synapses throughout the [3H]kainate binding sites does not match the AMPA receptor central nervous system by interacting with different types of distribution but corresponds well to the brain areas with high receptor channels. Cloning of glutamate receptors has pro- susceptibility to the neurotoxic actions of kainate (e.g., vided evidence for the existence of several structurally related hippocampal CA3 field) (13). However, patch-clamp record- subunit families, each composed of several members. It has ings from adult hippocampal neurons have revealed that been proposed that KA1 and KA2 and GluR-5, GluR-6, and native glutamate receptors are similar to the AMPA-type GluR-7 families represent subunit classes of high-affinity kain- recombinant glutamate receptors expressed from cDNA ate receptors and that in vivo different kainate receptor sub- clones but have failed so far to detect receptor channels ofthe types might be constructed from these subunits in heteromeric kainate type (14, 15). The only apparently high-affinity kain- assembly. However, despite some indications from autoradio- ate receptor channels have been found in the peripheral graphic studies and binding data in brain membranes, no nervous system (16, 17), although they are also activated by functional pure kainate receptors have so far been detected in AMPA.
    [Show full text]
  • A Review of Glutamate Receptors I: Current Understanding of Their Biology
    J Toxicol Pathol 2008; 21: 25–51 Review A Review of Glutamate Receptors I: Current Understanding of Their Biology Colin G. Rousseaux1 1Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada Abstract: Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 – 15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25–51) Key words: glutamate, glycine, GABA, glutamate receptors, ionotropic, metabotropic, NMDA, AMPA, review Introduction and Overview glycine), peptides (vasopressin, somatostatin, neurotensin, etc.), and monoamines (norepinephrine, dopamine and In the first decades of the 20th century, research into the serotonin) plus acetylcholine. chemical mediation of the “autonomous” (autonomic) Glutamatergic synaptic transmission in the mammalian nervous system (ANS) was an area that received much central nervous system (CNS) was slowly established over a research activity.
    [Show full text]
  • Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by Cdna Microarray Analysis
    Neuropsychopharmacology (2004) 29, 1070–1079 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $25.00 www.neuropsychopharmacology.org Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis ´ ´1 1 ,1 Marketa Marvanova , Merja Lakso and Garry Wong* 1AI Virtanen Institute for Molecular Sciences, Department of Neurobiology, Laboratory of Functional Genomics and Bioinformatics, University of Kuopio, Kuopio, Finland In this study, we monitored gene expression profiles using cDNA microarrays after an acute systemic administration of the high affinity N-methyl-D-aspartate (NMDA) uncompetitive antagonist MK-801 (1 mg/kg; 4 h), and the clinically used moderate affinity antagonist memantine (25 mg/kg; 4 h) in adult rat brains. From a microarray containing 1090 known genes, 13 genes were regulated by both treatments of which 12 were upregulated and one was downregulated. In addition, 28 and 34 genes were regulated (X1.5- or p0.67- fold change) by either memantine or MK-801, respectively. Genes commonly regulated by both treatments and not previously reported were confirmed by in situ hybridization (ISH) and include regenerating liver inhibitory factor-1 (RL/IF-1), GDP-dissociation inhibitor 1 2 þ þ þ (GDI-1), neural visinin Ca -binding protein 2 (NVP-2), neuromedin B receptor, and Na /K transporting ATPase 2b. ISH with memantine (5–50 mg/kg) revealed regulation of these genes in other cortical and hippocampal regions. RL/IF-1 induction occurred at 1 h and returned to basal levels by 8 h, consistent with the profile of an immediate early gene.
    [Show full text]
  • Sensitization to Apomorphine, Effects of Dizocilpine NMDA Receptor Blockades Martin J
    Sensitization to apomorphine, effects of dizocilpine NMDA receptor blockades Martin J. Acerbo*, Jennifer M. Lee, Juan D. Delius Allgemeine P.I'ychoiogie, Un.iversiti:it KOl'lsrall Z, 78457 KOllstal'lZ, Germany Abstract The dopamine agonist apomorphine (apo) eli cits bouts of stereotyped pecking in pigeons, a response which increases with sllccessive apo injections. This sensitization is strongly context-specific and has been suggested to arise through a Pavlovian conditioning to both extern al and internal cues. We hypothetized that thi s learning involves dopamino-glutamatergic interactions and investigated the issue by inducing NMDA glutamate receptor blockades with the antagonist dizocilpine (diz). A first experiment examined the effects that four different doses (ranging between 0.05 and 0.1 2 mg/kg) of di z co-administered with a standard dose of 0.5 mg/kg of apo had on the development of the incremented response and on the later expression of the conditioned pecking response. Both responses were impaired by doses of around 0.10 mg/kg diz. A second experiment assessed whether either a di z treatment or a diz plus apo co-treatment affected the development of a subsequent sensitization to apo. The first treatment had no effect on the latter sensiti zation. A part sensitization that arose with the second treatment did not transfer to the final sensitization. The last experiment examined whether the administration of diz had an immediate effect on the incremented responding to apo and on the conditioned response shown by already sensitized pigeons. No effect was apparent with the first treatment, but there was a marked response inhibition with the second treatment.
    [Show full text]
  • Pentobarbitone Modulation of NMDA Receptors in Neurones Isolated from the Rat Olfactory Brain P
    Bridsh Joumal of Phamacology (1995) 116, 3005 - 3013 B 1995 Stockton Press All rights reserved 0007-1188/95 $12.00 S Pentobarbitone modulation of NMDA receptors in neurones isolated from the rat olfactory brain P. Charlesworth, *I. Jacobson & 'C.D. Richards Department ofPhysiology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF and *Department of Anatomy and Cell Biology, University of Goteborg, Medicinaregatan 5, S 413 90, Goteborg, Sweden 1 The action of pentobarbitone on the N-methyl-D-aspartate (NMDA) receptors of neurones freshly dissociated from the olfactory bulb and olfactory tubercle has been studied using patch-clamp techniques. 2 Pentobarbitone produced a concentration-dependent depression of the currents evoked by NMDA with an IC50 value of c. 250 uM. 3 Analysis of the NMDA-evoked noise produced power spectra that could be fitted by the sum of two Lorentzians with corner frequencies of 17 and 82 Hz. Pentobarbitone increased the corner frequency of the high frequency component but did not alter the apparent single channel conductance estimated from the noise. 4 Single channel recordings in either the cell-attached or outside-out patch configurations revealed that NMDA (20 or 50 gM) opened channels with a main conductance level around 55 pS and a principal subconductance around 44 pS. The uncorrected mean open time of the channels was 3.4 ms and mean burst length was 6.0 ms. Mean cluster length was about 12 ms. 5 Pentobarbitone produced a concentration-dependent reduction in both mean open time and burst length. Mean cluster length was much less affected.
    [Show full text]
  • Ketamine: Translating Mechanistic Discoveries Into the Next Generation of Glutamate Modulators for Mood Disorders
    Molecular Psychiatry (2017) 22, 324–327 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1359-4184/17 www.nature.com/mp GUEST EDITORIAL Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders Molecular Psychiatry (2017) 22, 324–327; doi:10.1038/mp.2016.249; identifying alternate targets for drug discovery with the goal of published online 10 January 2017 maintaining ketamine’s favorable therapeutic profile but eliminat- ing areas of concern associated with its use, such as dissociative side effects and abuse potential.15 Some of the alternate theories Over the last decade, numerous controlled studies have consis- currently being investigated to explain ketamine’s actions are tently described rapid, robust, and relatively sustained antide- explored in greater detail below. pressant response rates associated with single-dose ketamine The original preclinical evidence linking NMDA receptor infusions. Indeed, antidepressant response rates at 4, 24, and 72 h antagonism and ketamine’s rapid antidepressant effects led to a were 50%, 70%, and 35%, respectively, in individuals with decade of preclinical and clinical trials with NMDA receptor treatment-resistant depression (TRD) who received a single antagonists. During this time, ketamine’s antidepressant effects ketamine infusion.1,2 Furthermore, a recent meta-analysis of seven were consistently replicated in many pilot trials, and the onset and trials (encompassing 147 ketamine-treated patients) found that a offset of antidepressant efficacy with a single administration 1 single ketamine infusion produced rapid, yet transient, antide- became well characterized; such studies also helped characterize pressant effects, with odds ratios for response and transient the side effects associated with ketamine and the time frame in remission of symptoms at 24 h equaling 9.87 (4.37–22.29) and which these were likely to occur.
    [Show full text]
  • 1 Dextromethorphan and Dextrorphan Influence Insulin Secretion By
    JPET Fast Forward. Published on July 14, 2020 as DOI: 10.1124/jpet.120.265835 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265835 Dextromethorphan and dextrorphan influence insulin secretion by interacting with 2+ KATP and L-type Ca channels in pancreatic β-cells Anne Gresch, Martina Düfer University of Münster, Pharmaceutical and Medicinal Chemistry, Dept. of Pharmacology, Corrensstraße 48, 48149 Münster, Germany Downloaded from jpet.aspetjournals.org at ASPET Journals on September 30, 2021 1 JPET Fast Forward. Published on July 14, 2020 as DOI: 10.1124/jpet.120.265835 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265835 Running Title: NMDA receptor antagonists and β-cells Section assignment for table of contents: Endocrine and Diabetes Address correspondence to: Prof. Dr. Martina Düfer Pharmaceutical and Medicinal Chemistry, Dept. of Pharmacology PharmaCampus Corrensstraße 48, 48149 Münster, Germany Downloaded from Phone: +49 251 83 33339; Fax: +49 251 83 32144 [email protected] jpet.aspetjournals.org Text pages: 18 Tables: 0 at ASPET Journals on September 30, 2021 Figures: 6 References: 42 Word count: Abstract: 250 Introduction: 614 Discussion: 1712 Key words: β-cell, cytosolic calcium, dextromethorphan, insulin secretion, NMDA receptor, KATP channel Abbreviations: a.u.: arbitrary fluorescence units, DXM: dextromethorphan, DXO: dextrorphan, FOPP: fraction of plateau phase, MEA: microelectrode array, NMDA: N-methyl- D-aspartate, SUR1-KO: sulfonylurea receptor 1 knockout 2 JPET Fast Forward. Published on July 14, 2020 as DOI: 10.1124/jpet.120.265835 This article has not been copyedited and formatted.
    [Show full text]
  • Dizocilpine, Ketamine and Ethanol Reverse Nmda-Induced Eeg Changes and Convulsions in Rats and Mice
    Indian J Physiol Pharmacol 1991; 35(2): 111-116 DIZOCILPINE, KETAMINE AND ETHANOL REVERSE NMDA-INDUCED EEG CHANGES AND CONVULSIONS IN RATS AND MICE AVADHESH C. SHARMA, SANJAY N. THORAT, USHA NAYAR* AND SHRINIVAS K. KULKARNI** Pharmacology Division, Department of Pharmaceutical Sciences, Panjab Univer~ity, Chandigarh - 160014 and *Department of Physiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029 ( Received on January 7, 1991 ) Abstract: Electroencephalographic (EEG) activity in neocortex of rats following intracerebroventricular (icv) administration of NMDA (0.25-2 nmoV10 ,...1) and its modification by noncompetitive NMDA-receptor antagonists, dizocilpine (MK-801) (0.025-0.1 mglkg, ip) and ketamine (10-50 mglkg, ip) was recorded at 0, 0.5,4,8 and 24 hr with chronically implanted electrodes. NMDA (0.25 and 1 nmol) showed longer lasting decrease in frequency in cortical neurons while 2 nmol produced convulsions and death. Administration of MK 801 (0.05 mg/kg) and ketamine (50 mglkg) prior to NMDA offered protecton in 40% of animals against NMDA-induced convulsions and blocked NMDA-induced long term influence. However, ketamine and MK 801 showed an increase in percent amplitude and also had long lasting effects per se. In conscious mice, NMDA (0.5-10 nmoV,...1 icv) induced dose dependent convulsions. Both MK 801 and ketamine showed po­ tent anticonvulsant effect. Ethanol (0.5-2g1kg, ip) also offered significant protection against NMDA-in­ duced convulsions. MK 801 (0.1 mglkg) when administered concurrently with ethanol (0.5 glkg) exhibited synergistic anticonvulsant effect. The EEG study in rats and effect of NMDA in conscious mice provide a direct evidence for the role of NMDA-receptor system in convulsions and in anticonvulsant action of ethanol.
    [Show full text]
  • Modulation of NMDA Receptor Activity in Fibromyalgia
    biomedicines Review Modulation of NMDA Receptor Activity in Fibromyalgia Geoffrey Littlejohn * and Emma Guymer Departments of Medicine, Monash University and Rheumatology, MonashHealth, Melbourne 3168, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-03-9594-2575 Academic Editor: Kim Lawson Received: 23 February 2017; Accepted: 7 April 2017; Published: 11 April 2017 Abstract: Activation of the N-methyl-D-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is a target for therapeutic intervention. A literature review of interventions impacting on the NMDAR shows a number of drugs to be active on the NMDAR mechanism in fibromyalgia patients, with variable clinical effects. Low-dose intravenous ketamine and oral memantine both show clinically useful benefit in fibromyalgia. However, consideration of side-effects, logistics and cost need to be factored into management decisions regarding use of these drugs in this clinical setting. Overall benefits with current NMDAR antagonists appear modest and there is a need for better strategy trials to clarify optimal dose schedules and to delineate potential longer–term adverse events. Further investigation of the role of the NMDAR in fibromyalgia and the effect of other molecules that modulate this receptor appear important to enhance treatment targets in fibromyalgia. Keywords: fibromyalgia; drugs; NMDA receptor; ketamine; memantine 1. Introduction There are multiple pain-related mechanisms that are active in patients with fibromyalgia. The relative contribution of each mechanism appears to vary between patients.
    [Show full text]