Targeting glutamate system for novel antipsychotic approaches: Relevance for residual psychotic symptoms and treatment resistant schizophrenia

Bartolomeis, Andrea de; Sarappa, Chiara; Magara, Salvatore; Iasevoli, Felice

doi:10.1016/j.ejphar.2012.02.033

Cited by 63 publications

(44 citation statements)

References 125 publications

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“…Despite antagonism at D2 receptors is considered the main mechanism of antipsychotics action, converging evidence suggests that antipsychotics may affect multiple signaling pathways [2,[197][198][199]. Several gene expression studies on antipsychotic-treated animals point to the induction of genes associated with neurotransmission, signal transduction, and synaptic plasticity, suggesting that a range of mechanisms are involved in antipsychotic activity and are possibly associated with the occurrence of side effects [125-127, 181, 200, 201].…”

Section: Future Treatment Direction: Mirnas As Potential Antipsychotimentioning

confidence: 99%

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

et al. 2014

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Despite dopamine-glutamate aberrant interaction that has long been considered a relevant landmark of psychosis pathophysiology, several aspects of these two neurotransmitters reciprocal interaction remain to be defined. The emerging role of postsynaptic density (PSD) proteins at glutamate synapse as a molecular "lego" making a functional hub where different signals converge may add a new piece of information to understand how dopamine-glutamate interaction may work with regard to schizophrenia pathophysiology and treatment. More recently, compelling evidence suggests a relevant role for microRNA (miRNA) as a new class of dopamine and glutamate modulators with regulatory functions in the reciprocal interaction of these two neurotransmitters. Here, we aimed at addressing the following issues: (i) Do miRNAs have a role in schizophrenia pathophysiology in the context of dopamine-glutamate aberrant interaction? (ii) If miRNAs are relevant for dopamine-glutamate interaction, at what level this modulation takes place? (iii) Finally, will this knowledge open the door to innovative diagnostic and therapeutic tools? The biogenesis of miRNAs and their role in synaptic plasticity with relevance to schizophrenia will be considered in the context of dopamine-glutamate interaction, with special focus on miRNA interaction with PSD elements. From this framework, implications both for biomarkers identification and potential innovative interventions will be considered.

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Section: Future Treatment Direction: Mirnas As Potential Antipsychotimentioning

confidence: 99%

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

et al. 2014

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“…Homer1b and PSD-95 are key PSD molecules involved in synaptic rearrangements underlying dendritic spine growth and synaptic strength [7,49], and the downregulation of Homer1b has been found to attenuate glutamate-mediated excitotoxicity in rat cortical neurons [50]. Furthermore, recent studies explain how excitotoxicity appears strongly linked to a reduction of BDNF, which plays an important role in survival of striatal neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent meta-analysis indicates that schizophrenia is associated with glutamate level increase in several brain regions [6]. Glutamate is the main excitatory neurotransmitter in human CNS and it plays a prominent role in synaptic plasticity, learning, and memory and other cognitive functions [7]. It has been also involved in excitotoxicity and neuroprotection processes [8].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of memantine in schizophrenic patients: A systematic review

et al. 2017

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Several evidences support the hypothesis that glutamatergic dysfunction may be implicated in the pathogenesis of schizophrenia and in the last few years great interest has been focused on the role of the N-methyl-D-aspartate receptor (NMDAR). Glutamate is the main excitatory neurotransmitter in human CNS and it plays a prominent role in synaptic plasticity, learning, and memory and other cognitive functions. Increasing interest in memantine add-on therapy in schizophrenic patients with negative and cognitive symptoms may suggest that memantine could be a new promising treatment in schizophrenia. The aim of this update was to evaluate clinical data about the memantine effectiveness in schizophrenic patients. Our systematic review of the literature highlights that memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.

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“…Modulation of NMDA receptor function is thus considered to possess an important potential in the treatment of pathological states such as pain, stroke and neurogenerative diseases (Tarawneh and Galvin 2010;Lai et al 2011;Petrenko et al 2014). In addition, the NMDA receptor is proposed as a potential complementary target in the treatment of psychiatric disorders such as schizophrenia (de Bartolomeis et al 2012) or depression (Sanacora et al 2012;Ghasemi et al 2014). As a function of the indication, possible therapeutic interventions include both a direct targeting of NMDA receptors by specific ligands or more indirect approaches, exemplified by glycine transporter inhibitors such as the recently tested bitopertin (Balu and Coyle 2014).…”

Section: Introductionmentioning

confidence: 99%

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

Heusler

Tourette

Cussac

2015

Naunyn-Schmiedeberg's Arch Pharmacol

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N-methyl-D-aspartate (NMDA) receptor channels are implicated in a wide range of physiological and pathophysiological processes, and a large number of pharmacological agents have been introduced that target the receptor via diverse mechanisms of action. Amongst others, subunit selectivity (in particular for the NR2B receptor subunit) and rapid unblocking kinetics have been put forward as favourable pharmacological properties of NMDA receptor-targeting drugs. Here, we describe a pharmacological characterization of human recombinant NMDA receptors expressed in Xenopus oocytes in an electrophysiological set-up. Using this approach, we compare inhibitor potencies of several known NMDA receptor ligands as well as unblocking kinetic properties of selected compounds. All compounds tested had similar potencies at receptors containing NR2A or NR2B receptors with the exception of traxoprodil, which was selective for NR2B. The rank order of potency was (+)MK-801 > phencyclidine (PCP) ≈ traxoprodil > memantine ≈ ketamine > duloxetine. In line with its proposed rapid dissociation properties, the relatively well-tolerated drug memantine exhibits markedly faster unblocking than ketamine and PCP, similar to the low-affinity compound, duloxetine. Electrophysiological recording in Xenopus oocytes thus allows a relatively convenient comparison of key pharmacological parameters at recombinant human NMDA receptors.

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Targeting glutamate system for novel antipsychotic approaches: Relevance for residual psychotic symptoms and treatment resistant schizophrenia

Cited by 63 publications

References 125 publications

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

Efficacy of memantine in schizophrenic patients: A systematic review

Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

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