Blockade of GluN2B-containing NMDA receptors reduces short-term brain damage induced by early-life status epilepticus

Loss, Cássio Morais; Rosa, N.S.; Mestriner, Régis Gemerasca; Xavier, Léder Leal; Oliveira, Diogo Lösch de

doi:10.1016/j.neuro.2019.01.002

Cited by 13 publications

(9 citation statements)

References 60 publications

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“…In principle, these pro-maturational effects could be useful for restoring stable synaptic networks in pathologies where a shift towards immature circuits and/or to GluN2B-dependent neurotoxicity occurs. Thus, in animal models of temporal lobe epilepsy, the GluN2B/GluN2A ratio increased in several forebrain regions (Amakhin et al, 2017; Zubareva et al, 2018), and synapses enriched in GluN2B subunits favored seizure susceptibility (Okuda et al, 2017), whereas blockade of GluN2B receptors during experimental status epilepticus with compounds that included the rapid acting antidepressant ketamine (a non-selective NMDA-R antagonist) reduced neuronal damage (Loss et al, 2019). Moreover, fluoxetine and other SSRIs are considered to be safe in the treatment of depression in epileptic patients, although exceptions (e.g., in some epilepsy subtypes) to this general rule might exist (Kanner, 2016a; Kanner, 2016b).…”

Section: Discussionmentioning

confidence: 99%

Chronic Fluoxetine Treatment Induces Maturation-Compatible Changes in the Dendritic Arbor and in Synaptic Responses in the Auditory Cortex

et al. 2019

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Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat mood and anxiety disorders. Chronic treatment with this antidepressant drug is thought to favor functional recovery by promoting structural and molecular changes in several forebrain areas. At the synaptic level, chronic fluoxetine induces an increased size and density of dendritic spines and an increased ratio of GluN2A over GluN2B N-methyl-D-aspartate (NMDA) receptor subunits. The “maturation”-promoting molecular changes observed after chronic fluoxetine should also induce structural remodeling of the neuronal dendritic arbor and changes in the synaptic responses. We treated adult rats with fluoxetine (0.7 mg/kg i.p. for 28 days) and performed a morphometric analysis using Golgi stain in limbic and nonlimbic cortical areas. Then, we focused especially on the auditory cortex, where we evaluated the dendritic morphology of pyramidal neurons using a 3-dimensional reconstruction of neurons expressing mRFP after in utero electroporation. With both methodologies, a shortening and decreased complexity of the dendritic arbors was observed, which is compatible with an increased GluN2A over GluN2B ratio. Recordings of extracellular excitatory postsynaptic potentials in the auditory cortex revealed an increased synaptic response after fluoxetine and were consistent with an enrichment of GluN2A-containing NMDA receptors. Our results confirm that fluoxetine favors maturation and refinement of extensive cortical networks, including the auditory cortex. The fluoxetine-induced receptor switch may decrease GluN2B-dependent toxicity and thus could be applied in the future to treat neurodegenerative brain disorders characterized by glutamate toxicity and/or by an aberrant network connectivity.

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Section: Discussionmentioning

confidence: 99%

Chronic Fluoxetine Treatment Induces Maturation-Compatible Changes in the Dendritic Arbor and in Synaptic Responses in the Auditory Cortex

et al. 2019

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“…Those GluN2B heteromers showed a significant loss of ion-channel block by extracellular Mg 2+ and a significant increase of Ca 2+ permeability (Lemke et al, 2014). Meanwhile, blocking GluN2B-containing NMDARs can reduce short-term brain injury caused by early-life SE (Loss et al, 2019).…”

Section: Genetic Mutations Of Nmdar In Epilepsymentioning

confidence: 99%

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Chen

Liu

et al. 2022

Front. Mol. Neurosci.

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Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

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“…Ketamine began to be abused as a dissociative psychotomimetic in the late 1970s, primarily by soldiers in the Vietnam War (where it was widely used as a battle-field analgesic/anesthetic), and on the East Coast of the United States (Mion, 2017). The Drug Enforcement Agency classifies ketamine as a Schedule III drug because of its low to moderate potential for dependence (Lopez and Tadi, 2020). Ketamine's anesthetic effects require infusions at a rate of ∼1 mg/kg/hr, and its low cost has made it useful for surgeries in low-resource settings, in pediatric age groups, and in those vulnerable to hypotension.…”

Section: On the History Of Ketaminementioning

confidence: 99%

Ketamine: Neuroprotective or Neurotoxic?

et al. 2021

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Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.

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Blockade of GluN2B-containing NMDA receptors reduces short-term brain damage induced by early-life status epilepticus

Cited by 13 publications

References 60 publications

Chronic Fluoxetine Treatment Induces Maturation-Compatible Changes in the Dendritic Arbor and in Synaptic Responses in the Auditory Cortex

Chronic Fluoxetine Treatment Induces Maturation-Compatible Changes in the Dendritic Arbor and in Synaptic Responses in the Auditory Cortex

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Ketamine: Neuroprotective or Neurotoxic?

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