Amanda L. Barth (United States of America)
Aptinyx, Inc.
Research
Amanda Barth, PhD is the Senior Director of Research at Aptinyx, Inc. Their research is focused on the study of NMDA receptor modulation and the development of novel compounds for the treatment of CNS disorders, including painful diabetic peripheral neuropathy, fibromyalgia, PTSD, and cognitive impairment associated with Parkinson's Disease.

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THE NMDA RECEPTOR POSITIVE ALLOSTERIC MODULATOR NYX-458 RESCUES AGE-RELATED SYNAPTIC DYSFUNCTION VIA CAMKIIΒ-MEDIATED SIGNALING IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS

Session Name
1980 - ADVANCES IN PD AND LBD DRUG DEVELOPMENT 2 (ID 102)
Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
11:35 AM - 01:20 PM
Room
ONSITE: 114
Lecture Time
12:05 PM - 12:20 PM
Presenter

Abstract

Aims

Objectives: NYX-458, a positive allosteric modulator of the N-methyl-D-aspartate receptor (NMDAR), enhances NMDAR-mediated synaptic plasticity and is currently in Phase II clinical development for the treatment of mild dementia in Parkinson’s Disease and Lewy body dementia. NYX-458 enhances attention, working-memory, and cognitive flexibility in a primate model of Parkinson’s disease cognitive-impairment that depends on optimal activity in the prefrontal cortex (PFC) and hippocampus. This study sought to examine the molecular mechanism of action of NYX-458 within the PFC and hippocampus in a rodent model of age-related cognitive decline.

Methods

Methods: Male, 3-4-month-old (young) and 26-27-month-old (aged) F344 rats were assessed for changes in NMDAR-mediated plasticity and performance in the Morris water-maze (MWM) after oral dosing with NYX-458 (0.1-10 mg/kg, PO). Synaptic spine density and NMDAR-relevant protein levels were quantified in the hippocampus and PFC following learning assessments in the MWM.

Results

Results: NYX-458 enhances NMDAR-mediated current and plasticity within the PFC and enhances PFC-dependent learning in a novel object recognition assay. NYX-458 also enhances hippocampal plasticity specifically in aged F344 rats and hippocampal-dependent learning in the MWM. The dose of NYX-458 (1 mg/kg, PO) that improved MWM performance reversed age-related synaptic spine loss and increased CAMKIIβ-mediated signaling and resultant downstream effects on NMDAR2B and AMPAR trafficking in both the hippocampus and PFC of aged rats.

Conclusions

Conclusions: NYX-458 enhances synaptic plasticity mechanisms associated with hippocampal-dependent learning and memory and induces changes within the PFC as part of an interconnected network. These data support the development of NYX-458 for the treatment of cognitive decline.

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