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Pharmacology, Biochemistry, and Behavior Feb 2023Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are... (Review)
Review
Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are involved in the MDD pathophysiology. In this scenario, the glutamatergic system represents a promising therapeutic target for treatment-resistant depression. To our knowledge, this is the first study using semantic approach with systems biology to identify potential targets involved in the fast-acting antidepressant effects of ketamine and its enantiomers as well as identifying specific targets of (R)-ketamine. We performed a systematic review, followed by a semantic analysis and functional gene enrichment to identify the main biological processes involved in the therapeutic effects of these agents. Protein-protein interaction networks were constructed, and the genes exclusively regulated by (R)-ketamine were explored. We found that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits-Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by the three-antidepressant agents, reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects. Differential regulation of Transforming Growth Factor Beta 1 (TGF-β1) receptors-Mitogen-Activated Protein Kinases (MAPK's), Receptor Activator of Nuclear Factor-Kappa Beta Ligand (RANKL), and Serotonin Transporter (SERT) seems to be particularly involved in (R)-ketamine antidepressant effects. Our data helps further studies investigating the relationship between these targets and the mechanisms of (R)-ketamine and searching for other therapeutic compounds that share the regulation of these specific biomolecules. Ultimately, this study could contribute to improve the fast management of depressive-like symptoms with less detrimental side effects than ketamine and (S)-ketamine.
Topics: Humans; Ketamine; Depression; Depressive Disorder, Major; Systems Biology; Antidepressive Agents; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 36731751
DOI: 10.1016/j.pbb.2023.173523 -
Therapeutic Advances in... Apr 2014The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug... (Review)
Review
The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify 'classical' monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.
PubMed: 24688759
DOI: 10.1177/2045125313507739 -
American Journal of Health Behavior Mar 2020There is suggestive evidence that exercise may have a greater effect on visuo-spatial memory, compared to other memory types. However, we have a limited understanding...
There is suggestive evidence that exercise may have a greater effect on visuo-spatial memory, compared to other memory types. However, we have a limited understanding as to the mechanisms through which exercise may subserve visuo-spatial memory. Thus, the purpose of this review is to evaluate the extent to which exercise may influence visuo-spatial memory, whether exercise can attenuate drug- and diseased-induced declines in memory, and determine the underlying mechanisms of these relationships. We employed a systematic review approach. We identified studies using electronic databases, including PubMed, PsychInfo, Sports Discus and Google Scholar. In total, we identified 32 articles. Among these, 2 were among humans and 30 were conducted in animal models. There was strong evidence sup- porting the facilitative role of chronic exercise in visuo-spatial memory improvements, as well as attenuation of drug- and diseased-induced memory decline. There are various mechanisms through which chronic exercise may influence visuo-spatial memory, including increased neuro-genesis, angiogenesis, improved neural efficiency, CB receptor signaling, activation of H₂ receptors, and increased number of synaptic structures (eg, AMPA and NMDA receptors). Exercise may help to enhance visuo-spatial memory.
Topics: Animals; Exercise; Exercise Therapy; Humans; Memory Disorders; Physical Conditioning, Animal; Spatial Memory
PubMed: 32019650
DOI: 10.5993/AJHB.44.2.5 -
Journal of Cerebral Blood Flow and... Jul 2018Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a...
Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.
Topics: Brain Injuries; Humans; Neuromuscular Depolarizing Agents; Neurons
PubMed: 29673289
DOI: 10.1177/0271678X18771440 -
Epilepsy & Behavior : E&B Sep 2018Perampanel (PER) is a noncompetitive β-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor antagonist with demonstrated efficacy in animal models of...
OBJECTIVE
Perampanel (PER) is a noncompetitive β-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor antagonist with demonstrated efficacy in animal models of status epilepticus (SE). We performed a systematic review of the literature to assess the efficacy and tolerability of PER in the treatment of refractory and super-refractory SE.
METHODS
We searched Medline, Embase, and CENTRAL (accessed from inception to April 30, 2018) to identify studies evaluating oral PER as treatment of SE of any type. We also searched the OpenGrey repository and conference proceedings of international congresses by the International League Against Epilepsy and by the American Epilepsy Society from 2012 onwards.
RESULTS
Ten articles were included, with a total of 69 episodes of SE occurring in 68 patients (aged 18 to 91 years). The type and etiology of SE varied remarkably across studies. The number of drugs used prior to PER ranged from 1 to 9. The time from SE onset to PER administration ranged from 9.25 h to 35 days. The initial PER dose ranged from 2 to 32 mg. The proportion of patients achieving clinical SE cessation varied from 17% to 100%. The time from PER administration to SE cessation ranged from 1 h to 4 weeks.
CONCLUSIONS
The currently available evidence supporting the use of PER in SE is weak and hampered by several confounding factors. Further studies should be performed in more clinically homogeneous and larger cohorts to evaluate the efficacy and safety of PER administered in earlier stages of SE, at higher dosages, and at intervals shorter than 24 h.
Topics: Animals; Anticonvulsants; Humans; Nitriles; Pyridones; Receptors, AMPA; Status Epilepticus; Treatment Outcome
PubMed: 30076046
DOI: 10.1016/j.yebeh.2018.07.004 -
Frontiers in Neurology 2019Autoimmune encephalitides (AIE) comprise a group of inflammatory diseases of the central nervous system (CNS), which can be further characterized by the presence of...
Autoimmune encephalitides (AIE) comprise a group of inflammatory diseases of the central nervous system (CNS), which can be further characterized by the presence of different antineuronal antibodies. Recently, a clinical approach for diagnostic criteria for the suspected diagnosis of AIE as well as definitive AIE were proposed. These are intended to guide physicians when to order the antineuronal antibody testing and/or facilitate early diagnosis even prior to the availability of the specific disease-confirming test results to facilitate prompt treatment. These diagnostic criteria also include the results of basic cerebrospinal fluid (CSF) analysis. However, the different antibody-defined AIE subtypes might be highly distinct with regard to their immune pathophysiology, e.g., the pre-dominance of specific IgG subclasses, IgG1, or IgG4, or frequency of paraneoplastic compared to idiopathic origin. Thus, it is conceivable that the results of basic CSF analysis might also be very different. However, this has not been explored systematically. Here, we systematically reviewed the literature about the 10 most important AIE subtypes, AIE with antibodies against NMDA, AMPA, glycine, GABA, and GABA receptors as well as DPPX, CASPR2, LGI1, IgLON5, or glutamate decarboxylase (GAD), with respect to the reported basic CSF findings comprising CSF leukocyte count, total protein, and the presence of oligoclonal bands (OCB) restricted to the CSF as a sensitive measure for intrathecal IgG synthesis. Our results indicate that these basic CSF findings are profoundly different among the 10 different AIE subtypes. Whereas, AIEs with antibodies against NMDA, GABA, and AMPA receptors as well as DPPX show rather frequent inflammatory CSF changes, in AIEs with either CASPR2, LGI1, GABA, or glycine receptor antibodies CSF findings were mostly normal. Two subtypes, AIEs defined by either GAD, or IgLON5 antibodies, did not fit into this general pattern. In AIE with GAD antibodies, positive OCBs in the absence of other changes were typical, while the CSF in IgLON5 antibody-positive AIE was characterized by elevated protein.
PubMed: 31404257
DOI: 10.3389/fneur.2019.00804 -
PloS One 2019Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent...
Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.
Topics: Amygdala; Animals; Behavior, Animal; Cannabinoid Receptor Antagonists; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fear; Hippocampus; Male; Memory; Models, Animal; Rats; Receptor, Cannabinoid, CB1; Receptors, AMPA; Rimonabant; Time Factors
PubMed: 30645588
DOI: 10.1371/journal.pone.0205781 -
Frontiers in Psychiatry 2022The mechanism of action underlying ketamine's rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar...
The mechanism of action underlying ketamine's rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.
PubMed: 35546951
DOI: 10.3389/fpsyt.2022.860882