A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulates the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the modulation of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors predominantly on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are blocked an increase of Gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but also to synchronous states with no apparent gamma. We conclude that NMDA antagonists induce increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers

Mutations in N-methyl-d-aspartate receptors (NMDAR) subunits have been implicated in a growing number of human neurodevelopmental disorders. Previously, a de novo mutation in GRIN2A, encoding the GluN2A subunit, was identified in a patient with severe epilepsy and developmental delay. This missense mutation, which leads to GluN2A-P552R, produces significant dendrotoxicity in transfected rodent cortical neurons, as evidenced by pronounced dendritic blebbing. This injurious process can be prevented by treatment with the NMDA antagonist memantine. Given the increasing use of FDA approved NMDA antagonists to treat patients with GRIN mutations, who may have seizures refractory to traditional anti-epileptic drugs, we investigated whether additional NMDA antagonists were effective in attenuating neurotoxicity associated with GluN2A-P552R expression. Intriguingly, we found that while treatment with memantine can effectively block GluN2A-P552R-mediated dendrotoxicity, treatment with ketamine does not, despite the fact that both drugs work as open NMDAR channel blockers. Interestingly, we found that neurons expressing GluN2A-P552R were more vulnerable to an excitotoxic insult—an effect that, in this case, could be equally rescued by both memantine and ketamine. These findings suggest that GluN2A-P552R induced dendrotoxicity and increased vulnerability to excitotoxic stress are mediated through two distinct mechanisms. The differences between memantine and ketamine in halting GluN2A-P552R dendrotoxicity could not be explained by NMDA antagonist induced changes in MAP or Src kinase activation, previously shown to participate in NMDA-induced excitotoxicity. Our findings strongly suggest that not all NMDA antagonists may be of equal clinical utility in treating GRIN2A-mediated neurological disorders, despite a shared mechanism of action.

Review of Pharmacotherapy for Tinnitus

Various medications are currently used in the treatment of tinnitus, including anesthetics, antiarrhythmics, anticonvulsants, antidepressants, antihistamines, antipsychotics, anxiolytics, calcium channel blockers, cholinergic antagonists, NMDA antagonists, muscle relaxants, vasodilators, and vitamins. To date, however, no medications have been specifically approved to treat tinnitus by the US Food and Drug Administration (FDA). In addition, medicines used to treat other diseases, as well as foods and other ingested materials, can result in unwanted tinnitus. These include alcohol, antineoplastic chemotherapeutic agents and heavy metals, antimetabolites, antitumor agents, antibiotics, caffeine, cocaine, marijuana, nonnarcotic analgesics and antipyretics, ototoxic antibiotics and diuretics, oral contraceptives, quinine and chloroquine, and salicylates. This review, therefore, describes the medications currently used to treat tinnitus, including their mechanisms of action, therapeutic effects, dosages, and side-effects. In addition, this review describes the medications, foods, and other ingested agents that can induce unwanted tinnitus, as well as their mechanisms of action.

Repurposing Amantadine and Memantine for COVID-19: Guanylate Kinases Might Pave the Road towards Novel SARS CoV-2 and Anti Neoplastic Therapeutics.

Guanylate kinase 1 (GK1) was suggested to play a crucial role in SARS CoV-2 replication and previous studies have suggested a role in the pathogenesis of some neoplasms. We are providing a concise strengths, weaknesses, opportunities, and threats (SWOT) analysis of this hypothesis while discussing guanylate kinase physiological function, pharmacological importance. Importantly, though GK1 role in SARS CoV-2 replication might prove valid, the available experimental inhibitors of GK 1 might not, at least for the short term, be safely used to manage COVID-19. However, we suggest assessing another potential interaction between SARS CoV-2 and the non-authentic membrane-associated guanylate kinases as we suggest this might add to consider the potential role of the NMDA antagonists amantadine and memantine in COVID-19 management for and we have recommended clinical trials for selected described COVID-19 patients. Finally, we also recommend conducting genetic, physiological, and immunological studies to explore the long-term potentials of novel GK-1 inhibitors suggesting they might eventually lead to a novel COVID-19 and cancer pharmacotherapeutics.

Integrative review of the use of NMDA antagonists for TBI treatment

Introduction: The kinetic energy of TBI generates mechanical deformation, which causes release of glutamate, activating ionotropic receptors, principally NMDA receptors, favoring the flow of Ca++ and Na+ into the cell, producing edema. Then, the neurotoxicity generated by glutamate release can be avoided by NMDA antagonists. Objectives: To define if NMDA antagonists are promising for the treatment of TBI by literature analysis and to verify if there are reports of adverse reactions. Methodology: The review utilized the Scielo and Pubmed databases and the keywords used were: NMDA antagonist, Brain edema and Brain injury. The review contains 5 animal tests and 5 clinical studies. Results: Animal tests: CP-98,133 minimized edema, motor damage and is promising in the treatment of memory dysfunction after TBI. The NPS 1506 reduced edema in 24h, without altering the necrosis significantly. Ketamine decreased the volume of necrosis without altering the edema. HU-211 reduced the edema slightly. Clinical studies: NPS 1506 showed a neuroprotective profile and no serius effects. Traxoprodil decreased the mortality rate by 7%. CP-101.606 improved the patient’s condition, without adverse effects. Conclusion: Although NMDA antagonists demonstrate effectiveness in TBI treatment, more studies about adverse effects and efficiency are still needed. Among those analyzed, traxoprodil, NPS-1506 and CP-101.606 still don’t present serious adverse effects and demonstrate effectiveness, proving promising for new studies.

Review of synthetic approaches to dizocilpine

Abstract:: N-Methyl-D-aspartate (NMDA) receptors together with AMPA and kainite receptors belongs to the family of ionotropic glutamate receptors. NMDA receptors plays a crucial role in neuronal plasticity and cognitive functions. Overactivation of those receptors leads to glutamate induced excitotoxicity, which could be suppressed by NMDA antagonists. Dizocilpine was firstly reported in 1982 as a NMDA receptor antagonist with anticonvulsive properties, but due to serious side effects like neuronal vacuolization, its use in human medicine is restricted. However, dizocilpine is still used as validated tool to induce the symptoms of schizophrenia in animal models and also as a standart for comparative purposes to newly developed NMDA receptor antagonists. For this reason, synthesis of dizocilpine and specially its more active enantiomer (+)-dizocilpine is still relevant. In this review we bring a collection of various synthetic approaches leading to dizocilpine and its analogues.

Neurobiology of Anxiety Disorders

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.

Neurobiology of Anxiety Disorders

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.