NYX‐458 Improves Cognitive Performance in a Primate Parkinson's Disease Model

Abstract

A BS TRACT: Background: NYX-458 is a N-methyl-Daspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. Objectives: NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms. Methods: NYX-458 was evaluated in the chronic lowdose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with lowdose or high-dose levodopa to assess potential impact on motor symptoms. Results: NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. Conclusions: NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…A series of spirocyclic-b-lactams similar to the tetrapeptide GLYX-13 (rapastinel) have been reported to act as NMDA receptor PAMs (Khan et al, 2018;Barth et al, 2020). These compounds are suggested to potentiate both metabotropic and ionotropic NMDA receptor signaling, and the metabotropic activity may underlie potential therapeutic by enhancing synaptic plasticity (Bowers et al, 2020).…”

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

“…Regarding NYX-458, its administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function in a primate PD model. The phase II study is currently recruiting to test the safety and tolerability of NYX-458 but also activity across multiple neurocognitive assessments in people with mild cognitive impairment and mild dementia associated with PD and dementia with Lewy bodies (NCT04148391) [ 311 ].…”

Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update

“…In addition to the dopaminergic neuronal loss in PD, dysregulation of NMDAR in the cortical-striatal-pallidal-thalmo-cortical network and changes in plasticity of the brain regions are also crucial for cognitive function [ 103 ]. NMDAR modulators enhance synaptic plasticity [ 103 ]. We observed two trials in phase II that use NMDA receptor modulators (NYX-458 and DAAOI-P) in the PD treatment ( Table 1 ).…”

“…We observed two trials in phase II that use NMDA receptor modulators (NYX-458 and DAAOI-P) in the PD treatment ( Table 1 ). NYX-458 is an NMDAR modulator that increases cognitive properties and synaptic plasticity [ 103 , 104 ]. NYX-458 phase II trial plans to recruit PD subjects with mild cognitive impairments; the trial status shows the active recruiting and is estimated to complete by 22 December 2022 (NCT04148391).…”