Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia

Abstract

N-methyl-D-aspartate (NMDA) receptor hypofunction leading to neural network dysfunction is thought to play an important role in the pathophysiology of cognitive impairment associated with schizophrenia (CIAS). Increasing extracellular concentrations of the NMDA receptor co-agonist glycine through inhibition of glycine transporter-1 (GlyT1) has the potential to treat CIAS by improving cortical network function through enhanced glutamatergic signaling. Indeed, the novel GlyT1 inhibitor iclepertin (BI 425809) improved cognition in a recent clinical study in patients with schizophrenia. The present study tested the ability of iclepertin to reverse MK-801-induced deficits in auditory sensory processing and cortical network function using electroencephalography (EEG) to measure auditory event-related potentials (AERP) and 40 Hz auditory steady-state response (ASSR). In addition, improvements in memory performance with iclepertin were evaluated using the Tmaze spontaneous alternation test in MK-801-treated mice and the social recognition test in naïve rats. Iclepertin reversed MK-801-induced deficits in the AERP readouts N1 amplitude and N1 gating, as well as 40 Hz ASSR power and inter-trial coherence. Additionally, iclepertin significantly attenuated an MK-801-induced increase in basal gamma power. Furthermore, iclepertin reversed MK-801-induced working memory deficits in mice and improved social recognition memory performance in rats. Overall, this study demonstrates that inhibition of GlyT1 is sufficient to attenuate MK-801-induced deficits in translatable EEG parameters relevant to schizophrenia. Moreover, iclepertin showed memory-enhancing effects in rodent cognition tasks, further demonstrating the potential for GlyT1 inhibition to treat CIAS.

Antibiotics treatment promotes vasculogenesis in the brain of glioma-bearing mice

“…In order to validate the in vivo effect of glycine in promoting tumor growth and vasculogenesis, we tested the effect of a selective and orally active glycine transporter 1 (GlyT1) inhibitor [ 48 – 50 ]. It has been demonstrated that GlyT1 inhibitor is able to increase the plasma and cerebrospinal fluid glycine concentration in rats and humans [ 50 , 51 ].…”

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model

“…Compounds for which drug developers have followed this strategy have yielded promising results on electrophysiological measures as well as indices of social and cognitive functioning in patients and animal models. For instance, drugs increasing the synaptic concentration of the NMDAr co-agonists glycine and D-serine or acting on other aspects of the glutamatergic synapse are showing promising results on EEG and behavioral measures in preclinical and clinical trials for social and cognitive symptoms of SZ [64][65][66][67][68].…”

Beyond dopamine: Novel strategies for schizophrenia treatment

“…Iclepertin (BI 425809) is a GlyT-1 inhibitor developed by Boehringer Ingelheim specifically for the treatment of cognitive impairment accompanying schizophrenia. In preclinical trials, 104 iclepertin alleviated MK-801-induced deficits in EEG biomarkers related to cognitive functioning such as N1 amplitude and N1 gating. Moreover, it enhanced disrupted working and episodic memory in behavioral tasks in rodents.…”