The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development

Abstract

The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.

Neurosteroid‐sensitive δ‐GABAA receptors: A role in epileptogenesis?

“…This action of NMDAR blocker may be specifically related to receptor blockade or may relate to nonspecific actions on the neuronal dynamics during SE. NMDAR antagonists are known to affect EEG regardless of their ability to terminate SE . Indeed, in the current study, the power of EEG in certain frequencies was different between MK‐801‐treated and untreated animals.…”

“…NMDAR antagonists are known to affect EEG regardless of their ability to terminate SE. 28 Indeed, in the current study, the power of EEG Altered GABAergic transmission is proposed to play an important role in the disinhibition of DGCs during epileptogenesis. 29 The potential mechanisms contributing to the reduced GABAergic inhibition involve a loss of interneurons, the zinc-induced collapse of inhibition, and altered GABAR expression.…”

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

“…To facilitate the progression of BMS-986163, we examined effects on the qEEG. Previous studies have shown robust qEEG power band changes in monkeys treated with GluN2B NAMs (Keavy et al, 2016), and BMS-986163 produced the same pattern of response. As an approach, changes in qEEGrelated measures for NMDA receptor antagonists generally align well across species and, although not tested here, other measures such as auditory evoked potentials also have translational utility for GluN2B NAMs (Nagy et al, 2016).…”

“…qEEG Studies in Cynomolgus Monkeys. Studies to examine the effect of GluN2B NAM treatment on the qEEG response were conducted by BMS using methods described previously (Keavy et al, 2016). Six cynomolgus monkeys served as subjects for the qEEG studies, and each had been used previously in pharmacological studies, with a drug-free period of at least 1 month prior to testing.…”

Neuro-Feedback System Enhancing the Level of Symmetry in Left and Right Brain Activities

“…S tructure of Neurofeedback S ystem shooters [13]. Keavy et al suggested that neurofeedback could be used as a treatment, and although results using biofeedback cannot compete with drug therapy, there are significantly fewer side effects when it comes to ADHD therapy [14]. Zołubak et al proposed a prognostic expert system using neurofeedback signals, in which they addressed preliminary diagnostics issues using policy-based computing [15].…”