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

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-3ß, 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-3ß signaling pathway. CONCLUSIONS: These findings suggest that combination therapy for enhancing NMDA receptors may be able to rescue cognition deficit in schizophrenia. More studies are needed to better elucidate these mechanisms.

Neurotoxicity and apoptosis induced by pyrroloquinoline quinone and its ester derivative on primary cortical neurons.

Pyrroloquinoline quinone (PQQ) and its esterified derivative, PQQ ester (PQQE), have potential to treat or diagnose neurological and psychological disorders. However, their neurotoxicity remains unclear. To provide reference data for the brain targeting drug delivery techniques, the cytotoxic effects of PQQ and PQQE were examined in primary mouse cortical neurons. The results indicated that both PQQ and PQQE decreased neuron viability, reduced intracellular ATP level and disrupted the mitochondrial membrane potential in a concentration- and time-dependent manner, while PQQ was less potent than PQQE. PQQ and PQQE induced apoptosis involving increase of Bax, decrease of Bcl-2, release of mitochondrial cytochrome C into the cytosol, activation of caspase-3 and cleavage of PARP. A single mouse intracephalic injection of PQQ or PQQE showed similar results. Based on these findings, high-concentration PQQ or PQQE treatment could induce a wide range of neurotoxicity and apoptosis. The lowest observed adverse effect levels (LOAELs) of PQQ and PQQE were 10 µM and 2 µM respectively and the no observed adverse effect levels (NOAELs) were 5 µM and 1 µM respectively in mice cortical neurons.

PQQ ameliorates D-galactose induced cognitive impairments by reducing glutamate neurotoxicity via the GSK-3ß/Akt signaling pathway in mouse.

Oxidative stress is known to be associated with various age-related diseases. D-galactose (D-gal) has been considered a senescent model which induces oxidative stress response resulting in memory dysfunction. Pyrroloquinoline quinone (PQQ) is a redox cofactor which is found in various foods. In our previous study, we found that PQQ may be converted into a derivative by binding with amino acid, which is beneficial to several pathological processes. In this study, we found a beneficial glutamate mixture which may diminish neurotoxicity by oxidative stress in D-gal induced mouse. Our results showed that PQQ may influence the generation of proinflammatory mediators, including cytokines and prostaglandins during aging process. D-gal-induced mouse showed increased MDA and ROS levels, and decreased T-AOC activities in the hippocampus, these changes were reversed by PQQ supplementation. Furthermore, PQQ statistically enhanced Superoxide Dismutase SOD2 mRNA expression. PQQ could ameliorate the memory deficits and neurotoxicity induced by D-gal via binding with excess glutamate, which provide a link between glutamate-mediated neurotoxicity, inflammation and oxidative stress. In addition, PQQ reduced the up-regulated expression of p-Akt by D-gal and maintained the activity of GSK-3ß, resulting in a down-regulation of p-Tau level in hippocampus. PQQ modulated memory ability partly via Akt/GSK-3ß pathway.

Modulation of glycine sites enhances social memory in rats using PQQ combined with d-serine.

The aim of study was to investigate the effects of pyrroloquinoline quinone (PQQ) combined with d-serine on the modulation of glycine sites in the brain of rats using social recognition test. Rats were divided into seven groups (n=10) and given repeated intraperitoneal (ip) injections of saline, MK-801 (0.5mg/kg), clozapine (1mg/kg), haloperidol (0.1mg/kg), d-serine (0.8g/kg), PQQ (2.0µg/kg), or d-serine (0.4g/kg) combined with PQQ (1.0µg/kg) for seven days. A social recognition test, including assessment of time-dependent memory impairment, was performed. A non-competitive NMDA receptor antagonist, MK-801, significantly impaired social memory, and this impairment was significantly repaired with an atypical antipsychotic (clozapine) but not with a typical antipsychotic (haloperidol). Likewise, d-serine combined with PQQ significantly improved MK-801-disrupted cognition in naïve rats, whereas haloperidol was ineffective. The present results show that the co-agonist NMDA receptor treated with PQQ and d-serine enhances social memory and may be an effective approach for treating the cognitive dysfunction observed in schizophrenic patients. PQQ stimulates glycine modulatory sites by which it may antagonize indirectly by removing glycine from the synaptic cleft or by binding the unsaturated site with d-serine in the brain, providing the insights into future research of central nervous system and drug discovery.

Pyrroloquinoline quinone prevents MK-801-induced stereotypical behavior and cognitive deficits in mice.

Pyrroloquinoline quinone (PQQ), an essential nutrient, antioxidant, redox modulator, and nerve growth factor, prevents cognitive deficits associated with oxidative stress-induced neurodegeneration. Previous molecular imaging studies also demonstrate that PQQ binds to N-methyl D-aspartate (NMDA) receptors. In this study, we investigated the effects of PQQ on stereotypical behaviors and cognitive deficits induced by MK-801, a non-competitive NMDA antagonist used to model schizophrenia. Mice were given repeated injections of MK-801 (0.5mg/kg/d) and PQQ (0.2, 2.0, or 20 µg/kg/d) for 60 days. Behavior was evaluated using a variety of motor, social, and cognitive tests. We found that PQQ administration significantly attenuated MK-801-induced increases in stereotypical behavior and ataxia, suggesting a protective role of PQQ against MK-801-induced neuronal dysfunction and psychiatric disorders. Future studies are necessary to elucidate the underlying mechanisms of PQQ.