Antipsychotic-like effects of the N-methyl-d-aspartate receptor modulator neboglamine: An immunohistochemical and behavioural study in the rat

Chiusaroli, Riccardo; Garofalo, Paolo; Espinoza, Stefano; Neri, Elisa; Caselli, Gianfranco; Lanza, Marika

doi:10.1016/j.phrs.2009.12.010

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Another study showed that only BDNF exon IV is transcriptionally up-regulated in the hippocampus during the consolidation of fear learning, suggesting that BDNF exon usage is brain region specific and responds differently to environmental cues [74]. However, it is well established that there is a decrease in BDNF mRNA levels [75,76] in animals with cognitive impairment [77]. Here, we did not directly test learning, but it has been demonstrated that rapid changes of hippocampal BDNF occur in contextual learning [78], and its increased expression in fear conditioning is attributed to the modulation of exon IV [79].…”

Section: Discussionmentioning

confidence: 99%

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats

Pase

Teixeira

Roversi

et al. 2015

The Journal of Nutritional Biochemistry

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Section: Discussionmentioning

confidence: 99%

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats

Pase

Teixeira

Roversi

et al. 2015

The Journal of Nutritional Biochemistry

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“…PCP is an NMDAR antagonist that produces dose-dependent increases in locomotor activity ( Adams and Moghaddam, 1998 ); the PCP rodent model is sensitive to the activity of antipsychotics and positive NMDAR modulators ( Chiusaroli et al, 2010 ; Alberati et al, 2012 ). A subcutaneous injection of 2.5 mg/kg PCP significantly increased the locomotion activity in the OF test compared with the vehicle group ( Figure 8 ; red [PCP] vs black [vehicle], P < .001 1-way ANOVA followed by Dunnett’s test).…”

Section: Resultsmentioning

confidence: 99%

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

Burgdorf¹,

Zhang

Stanton

et al. 2022

International Journal of Neuropsychopharmacology

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Background The role of glutamatergic receptors in major depressive disorder (MDD) continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDARs) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity. Methods NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity rat hippocampal and medial prefrontal cortex (mPFC) slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test (FST) and the chronic social deficit (CSD) mouse model. Target engagement and the safety/tolerability profile was assessed using PCP-induced hyperlocomotion and rotarod rodent models. Results Following a single oral dose, zelquistinel (0.1–100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/CSF concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited PCP (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance. Conclusions Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation (LTP) of synaptic transmission.

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“…Neboglamine (XY-240) acts as a positive allosteric modulator at the glycine site of the NR. In a PCP model of psychotic behavior, neboglamine improved hyperlocomotion and induced rearing behavior similar to CLZ and haloperidol [158]. Neboglamine had been under development by the company Rottapharm Madaus, but a Phase II is currently on hold [19].…”

Section: Experimental Approachesmentioning

confidence: 99%

Glutamatergic agents for schizophrenia: current evidence and perspectives

Zink

Correll

2015

Expert Review of Clinical Pharmacology

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Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology, biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergic-modulating antipsychotics that fail to significantly improve negative and cognitive symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics modulate this system on several levels, as do mood stabilizers, including lamotrigine, topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to overcome for successfully leveraging glutamatergic agents for schizophrenia are patient selection, focus on positive symptoms and late disease stages, and dose-response relationships. Because glutamate guides processes of brain development and maturation, clinical research should focus on the at-risk mental state or first-episode psychosis, address cognition and negative symptoms and use monotherapy designs in parallel to augmentation strategies.

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Antipsychotic-like effects of the N-methyl-d-aspartate receptor modulator neboglamine: An immunohistochemical and behavioural study in the rat

Cited by 8 publications

References 34 publications

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

Glutamatergic agents for schizophrenia: current evidence and perspectives

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