Modulating NMDA receptors to treat MK-801-induced schizophrenic cognition deficit: effects of clozapine combining with PQQ treatment and possible mechanisms of action

Abstract

Background: Clozapine has remarkable efficacy on both negative and cognitive symptoms of schizophrenia due to its slight activation of NMDA receptor. In fact, much evidence to the contrary. NMDAR is a complex containing specific binding sites, which are regulated to improve negative symptoms and cognitive deficits associated with individuals affected by schizophrenia. PQQ is a powerful neuroprotectant that specifically binds with NMDA receptors in the brain to produce beneficial physiological and cognitive outcomes. The aim of this study was to enhance NMDAR function and improve cognitive ability in schizophrenia by PQQ combined with clozapine. Methods: Rats were divided into four groups (n = 5) including control (saline), model (MK-801, 0.5 mg•kg − 1 •d − 1), atypical antipsychotic (MK-801 (0.5 mg•kg − 1 •d − 1) + Clozapine (1.0 mg•kg − 1 •d − 1), and co-agonist NMDA receptor (MK-801 (0.5 mg•kg − 1 •d − 1) + Clozapine (0.5 mg•kg − 1 •d − 1) + PQQ (1.0 μg•kg − 1 •d − 1) group. Each group of rats was injected subcutaneously every day for 6 weeks. Behavior test, including stereotyped behavior, locomotor hyperactivity, learning and memory, was performed. The Western blot assay was performed to analyze the expression of GSK-3β, Akt, NMDAR1, and MGLUR in rat hippocampus. Results: Results indicated that clozapine and PQQ combination therapy can improve MK801-induced schizophrenia behavior including stereotyped behavior, locomotor hyperactivity and cognitive impairment. Furthermore, we found that modulating NMDA receptors could ameliorate the memory impairments in Mk-801 induced schizophrenia rats by reducing the expression of NMDAR1 and MGLUR3, decreasing hippocampal tau hyperphosphorylation and inhibiting apoptosis through Akt /GSK-3β signaling pathway.

Novel microRNAs targeting NMDA receptor subunits in animal models of schizophrenia

“…Female animals were included in the MAM model along with the males as there are very few reports on MAM models of schizophrenia using female animals [45,46]. Although the doses of 0.5 mg/Kg and 1.0 mg/Kg of MK-801 were used previously in separate studies, our study involves detailed comparative analysis of behaviour upon administration of these doses [29][30][31][32][47][48][49]. In our treatment regime, the washout period of 5 days ensures that the drug per se won't interfere with the behavior and hence the observed behavioral changes could be arising from the drug-induced changes in the brain tissue (Figure 4 and 5).…”

“…MK-801 is a non-competitive NMDAR channel blocker. It was intraperitoneally administered in two different doses -0.5 mg/Kg and 1.0 mg/Kg for five days based on previous reports [30][31][32][33]. The resulting blockage of NMDAR is expected to cause alterations in the brain similar to schizophrenia.…”

CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration

“…Chronic ketamine treatment has been previously shown to increase the GluN1/PSD95 and the GluN2A/PSD95 ratio, which is expected to impact calcium signaling ( Lisek et al, 2017 ). In addition, NMDA subunit protein expression increases after chronic MK801 ( Rammes et al, 2001 ; Zhou et al, 2020 ) or PCP ( Yu et al, 2002 ; Anastasio and Johnson, 2004 ) treatments, and this increase has been linked with hyperfunctional NMDA receptors ( Yu et al, 2002 ). On the other hand, studies have also shown inhibitory ( Ding et al, 2016 ; Liu et al, 2018 ; Sun et al, 2021 ) or no effects ( Uttl et al, 2018 ) of these drugs on NMDA subunit expression, possible associated with differences in the dosage regimen.…”

The Impact of the Combined Administration of 1MeTIQ and MK-801 on Cell Viability, Oxidative Stress Markers, and Glutamate Release in the Rat Hippocampus

“…NMDA receptor inhibitors such as ketamine and MK-801 are widely used to model schizophrenia in animals. After administration of these compounds, rodents develop cognitive disorders and symptoms resembling positive and negative symptoms of schizophrenia (Mansbach and Geyer 1989;Zhou et al 2020). MK-801, as an NMDA receptor inhibitor, causes a number of changes in the functioning of neurons, including an increase in glutamate release, which may lead to an increase in excitotoxicity, oxidative stress and, consequently, cell death.…”