Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain

Vasilescu, Andrei-Nicolae; Mallien, Anne Stephanie; Pfeiffer, Natascha; Lang, Undine E.; Gass, Peter; Inta, Dragoš

doi:10.1007/s00406-020-01180-5

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…These results indicate that zelquistinel has minimal risk of hyperexcitability (due to excessive positive NMDAR activation) or sedation/ataxia/disassociation (due to excessive NMDAR blockade). Interestingly, previous reports demonstrated that rapastinel can reverse or block effects of NMDAR antagonists such as ketamine-induced cognitive deficits and MK-801 neurotoxicity ( Rajagopal et al, 2016 ; Vasilescu et al, 2021 ). Consistent with its positive modulatory activity, zelquistinel also inhibited hyperlocomotion induced by the NMDAR antagonist phencyclidine.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In order to study dendritic pruning during brain maturation, several key neurodevelopmental animal models of SZ have been developed. Some neurodevelopmental models of SZ include the maternal immune activation model [ 5 ] or the use of antagonists of the n-methyl-D-aspartate (NMDA) receptors, such as MK-801 [ 6 ] ketamine [ 7 ] and phencyclidine [ 8 , 9 ] or prenatal methylazoxymethanol acetate exposure [ 10 , 11 , 12 , 13 ], with the latter being one of the most validated neurodevelopmental model of SZ, in terms of face, construct and predictive validity [ 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia

et al. 2022

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Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmitter-systems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychotic-symptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages.

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Mechanisms involved in the antidepressant-like action of orally administered 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) in male and female mice

da Costa Rodrigues,

da Conceição Oliveira,

dos Santos

et al. 2024

Psychopharmacology

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Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain

Cited by 3 publications

References 18 publications

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

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

Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia

Mechanisms involved in the antidepressant-like action of orally administered 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) in male and female mice

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