N-methyl-D-aspartate receptors and thymoquinone induce apoptosis and alteration in mitochondria in colorectal cancer cells.

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.

Acute MK-801 increases measures of both sign-tracking and goal-tracking in male Sprague-Dawley rats.

Sign-tracking is a Pavlovian conditioned approach behavior thought to be important in understanding cue-driven relapse to drug use, and strategies for reducing sign-tracking may have some benefit in preventing relapse. A previous study successfully employed the NMDA receptor antagonist MK-801 in preventing the development of sign-tracking (but not goal-tracking) in a conditioned approach task. In this study, we focused on whether MK-801 would have similar effects on previously established sign-tracking behavior. MK-801 was administered after training in a standard sign-/goal-tracking task using a retractable lever as a conditioned stimulus and a sucrose pellet as unconditioned stimulus. It was found that MK-801 increased measures of both sign- and goal-tracking in subjects who had previously learned the task. The NMDA receptor appears to play a complex role in governing behavior related to sign-tracking.

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice.

BACKGROUND: Muscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. METHODS: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. RESULTS: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. CONCLUSION: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

Chronic MK-801 administration provokes persistent deficits in social memory in the prairie vole (Microtus ochrogaster): A potential animal model for social deficits of schizophrenia.

The prairie vole (Microtus ochrogaster) is a rodent species that has been used extensively to study biological aspects of human social bonding. Nevertheless, this species has not been studied in the context of modeling social deficits characteristic of schizophrenia. Building on studies in rodents that show that sub-chronic administration of an NMDA receptor antagonist induces persistent behavioral and neurological characteristics of schizophrenia, we administered MK-801 (0.2 mg/kg, daily, for 7 days) or physiological saline to young adult (45 days old) virgin male voles. At 69 days of age, we paired these males with virgin females. 24 h later, we assessed the males' social investigation of each female across the first 5 min of a three-hour preference test, and side-by-side contact with each female during the last hour of the test. Unlike saline-treated males, MK-801-treated males did not preferentially investigate the unfamiliar female, indicating a deficit in social memory. Although males of both groups preferentially spent time with their female partner, regression analysis revealed that deficits in social memory predicted lower partner preference in MK-801-treated males. We interpret these results in the context of recent studies of the natural history of the prairie vole as well as in the context of cognitive deficits in schizophrenia and propose that the social component of episodic memory might influence an individual's capacity to form and maintain long-term social bonds.

Suppressive effect of Yokukansan on glutamate released from canine keratinocytes.

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown. Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment. Methods: Glutamate produced from CPEKs in the medium at 24 hours was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 hours was measured using radioisotope labeling. Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. In addition, EGCG could inhibit glutamate release from CPEKs. Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. In addition, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD.

Distinct changes in brain metabolism in patients with dementia and hearing loss.

INTRODUCTION: Previous studies have reported that hearing loss (HL) is associated with dementia, although the mechanistic underpinnings remain elusive. This study aimed to evaluate the changes in brain metabolism in patients with HL and different types of dementia. METHODS: Patients with cognitive impairment (CI) and HL treated at the university-based memory clinic from May 2016 to October 2021 were included. In total, 108 patients with CI and HL prospectively underwent audiometry, neuropsychological test, magnetic resonance imaging, and 18 F-fluorodeoxyglucose positron emission tomography. Twenty-seven individuals without cognitive impairment and hearing loss were enrolled as a control group. Multivariable regression was performed to evaluate brain regions correlated with each pathology type after adjusting for confounding factors. RESULTS: Multivariable regression analyses revealed that Alzheimer's disease-related CI (ADCI) was associated with hypometabolic changes in the right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and bilateral medial temporal lobe. Lewy body disease-related CI (LBDCI) and vascular CI were associated with hypermetabolic and hypometabolic changes in the ascending auditory pathway, respectively. In the pure ADCI group, the degree of HL was positively associated with abnormal increase of brain metabolism in the right MTG, whereas it was negatively associated with decreased brain metabolism in the right STG in the pure LBDCI group. CONCLUSION: Each dementia type is associated with distinct changes in brain metabolism in patients with HL.

Radix Bupleuri aqueous extract attenuates MK801-induced schizophrenia-like symptoms in mice: Participation of intestinal flora.

Schizophrenia (SCZ) is a psychotic mental disorder characterized by cognitive, behavioral, and social impairments. However, current pharmacological treatment regimens are subpar in terms of effectiveness. This study aimed to investigate the function of Radix Bupleuri aqueous extract in SCZ in mouse models. The SCZ mouse model was established by MK-801 injection and feeding of Radix Bupleuri aqueous extract or combined antibiotics. Radix Bupleuri aqueous extract significantly improved the aberrant behaviors and neuronal damage in SCZ mice, upregulated SYP and PSD-95 expression and BDNF levels in hippocampal homogenates, down-regulated DA and 5-HT levels, and suppressed microglial activation in SCZ mice. Moreover, Radix Bupleuri aqueous extract improved the integrity of the intestinal tract barrier. The 16 S rRNA sequencing of feces showed that Radix Bupleuri extract modulated the composition of gut flora. Lactobacillus abundance was decreased in SCZ mice and reversed by Radix Bupleuri aqueous extract administration which exhibited a significant negative correlation with IL-6, IL-1ß, DA, and 5-HT, and a significant positive correlation with BDNF levels in hippocampal tissues. The abundance of Parabacteroides and Alloprevotella was increased in SCZ mice. It was reversed by Radix Bupleuri aqueous extract administration, which exhibited a positive correlation with IL-6, IL-1ß, and 5-HT and a negative correlation with BDNF. In conclusion, Radix Bupleuri aqueous extract attenuates the inflammatory response in hippocampal tissues and modulates neurotransmitter levels, exerting its neuroprotective effect in SCZ. Meanwhile, the alteration of intestinal flora may be involved in this process, which is expected to be an underlying therapeutic option in treating SCZ.

The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice.

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.

NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

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

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

Apple Pomace Extract Improves MK-801-Induced Memory Impairment in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease that involves progressive cognitive decline accompanied by synaptic degeneration and impaired neurotransmission. Recent studies revealed that apple pomace, a waste byproduct of the apple processing industry, has beneficial health properties, but its potential to prevent and treat AD has not been determined. Herein, we examined the effects of apple pomace extract on N-methyl-D-aspartate receptor antagonist MK-801-induced memory impairment in mice. Repeated treatment with apple pomace extract for 7 days reversed the MK-801-induced impairment of associative memory and recognition memory. RNA sequencing revealed that repeated treatment with apple pomace extract altered the gene expression profile in the hippocampus of mice. Real-time PCR showed that apple pomace extract induced upregulation of the mRNA expression for Zfp125 and Gstp1. Furthermore, gene sets related to synapse and neurotransmission were upregulated by apple pomace extract. These findings indicate that apple pomace extract may be useful for the prevention and treatment of AD.

Ameliorative Effect of Cannabidiol on Topiramate-Induced Memory Loss: The Role of Hippocampal and Prefrontal Cortical NMDA Receptors and CREB/BDNF Signaling Pathways in Rats.

Cannabidiol (CBD) is a promising neurological agent with potential beneficial effects on memory and cognitive function. The combination of CBD and topiramate in the treatment of some neurological diseases has been of great interest. Since Topiramate-induced memory loss is a major drawback of its clinical application and the overall effect of the combination of CBD and topiramate on memory is still unclear, here we investigated the effect of CBD on topiramate-induced memory loss and the underlying molecular mechanisms. A one trial step-through inhibitory test was used to evaluate memory consolidation in rats. Moreover, the role of N-methyl-D-aspartate receptors (NMDARs) in the combination of CBD and topiramate in memory consolidation was evaluated through the intra-CA1 administration of MK-801 and NMDA. Western blot analysis was used to evaluate variations in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding protein (pCREB)/CREB ratio in the prefrontal cortex (PFC) and hippocampus (HPC). While the intraperitoneal (i.p.) administration of topiramate (50, 75, and 100 mg/kg) significantly reduced inhibitory time latency, the i.p. administration of CBD (20 and 40 mg/kg) could effectively reverse these effects. Similarly, the sub-effective doses of NMDA plus CBD (10 mg/kg) could improve the topiramate-induced memory loss along with an enhancement in BDNF and pCREB expression in the PFC and HPC. Contrarily, the administration of sub-effective doses of the NMDAR antagonist (MK-801) diminished the protective effects of CBD (20 mg/kg) on topiramate-induced memory loss associated with decreased BDNF and pCREB levels in the PFC and HPC. These findings suggest that CBD can improve topiramate-induced memory impairment, partially by the NMDARs of the PFC and HPC, possibly regulated by the CREB/BDNF signaling pathway.

Focused Ultrasound Stimulates the Prefrontal Cortex and Prevents MK-801-Induced Psychiatric Symptoms of Schizophrenia in Rats.

BACKGROUND AND HYPOTHESIS: Treatment of schizophrenia remains a major challenge. Recent studies have focused on glutamatergic signaling hypoactivity through N-methyl-D-aspartate (NMDA) receptors. Low-intensity pulsed ultrasound (LIPUS) improves behavioral deficits and ameliorates neuropathology in dizocilpine (MK-801)-treated rats. The aim of this study was to investigate the efficacy of LIPUS against psychiatric symptoms and anxiety-like behaviors. STUDY DESIGN: Rats assigned to 4 groups were pretreated with or without LIPUS for 5 days. The open field and prepulse inhibition tests were performed after saline or MK-801 (0.3 mg/kg) administration. Then, the neuroprotective effects of LIPUS on the MK-801-treated rats were evaluated using western blotting and immunohistochemical staining. STUDY RESULTS: LIPUS stimulation of the prefrontal cortex (PFC) prevented deficits in locomotor activity and sensorimotor gating and improved anxiety-like behavior. MK-801 downregulated the expression of NR1, the NMDA receptor, in rat medial PFC (mPFC). NR1 expression was significantly higher in animals receiving LIPUS pretreatment compared to those receiving only MK-801. In contrast, a significant increase in c-Fos-positive cells in the mPFC and ventral tegmental area was observed in the MK-801-treated rats compared to those receiving only saline; this change was suppressed by pretreatment with LIPUS. CONCLUSIONS: This study provides new evidence for the role of LIPUS stimulation in regulating the NMDA receptor and modulating c-Fos activity, which makes it a potentially valuable antipsychotic treatment for schizophrenia.

Mechanism of cognitive impairment and white matter damage in the MK-801 mice model of schizophrenia treated with quetiapine.

Schizophrenia has been linked to cognitive impairment and white matter damage in a growing number of studies this year. In this study, we used the MK-801-induced schizophrenia-like mice model to investigate the effects of quetiapine on behavioral changes and myelin loss in the model mice. The subjects selected for this study were C57B6/J male mice, MK-801 (1 mg/kg/d intraperitoneal injection) modeling for 1 week and quetiapine (10 mg/kg/d intraperitoneal injection) treatment for 2 weeks. Behavioral tests were then performed using the three-chamber paradigm test and the Y maze test. Moreover, western blot, immunohistochemistry, and immunofluorescence were conducted to investigate the changes in oligodendrocyte spectrum markers. In addition, we performed some mechanism-related proteins by western blot. Quetiapine ameliorated cognitive impairment and cerebral white matter damage in MK-801 model mice, and the mechanism may be related to the PI3K/AKT pathways. The present study suggests that quetiapine has a possible mechanism for treating cognitive impairment and white matter damage caused by schizophrenia.

The Post-conditioning Acute Strength Exercise Facilitates Contextual Fear Memory Consolidation Via Hippocampal N-methyl-D-aspartate-receptors.

The benefits of aerobic exercises for memory are known, but studies of strength training on memory consolidation are still scarce. Exercise stimulates the release of metabolites and myokines that reaching the brain stimulate the activation of NMDA-receptors and associated pathways related to cognition and synaptic plasticity. The aim of the present study was to investigate whether the acute strength exercise could promote the consolidation of a weak memory. We also investigated whether the effects of strength exercise on memory consolidation and on the BDNF and synapsin I levels depends on the activation of NMDA-receptors. Male Wistar rats were submitted to strength exercise session after a weak training in contextual fear conditioning paradigm to investigate the induction of memory consolidation. To investigate the participation of NMDA-receptors animals were submitted to contextual fear training and strength exercise and infused with MK801 or saline immediately after exercise. To investigate the participation of NMDA-receptors in BDNF and synapsin I levels the animals were submitted to acute strength exercise and infused with MK801 or saline immediately after exercise (in absence of behavior experiment). Results showed that exercise induced the consolidation of a weak memory and this effect was dependent on the activation of NMDA-receptors. The hippocampal overexpression of BDNF and Synapsin I through exercise where NMDA-receptors dependent. Our findings showed that strength exercise strengthened fear memory consolidation and modulates the overexpression of BDNF and synapsin I through the activation of NMDA-receptors dependent signaling pathways.

Effects of Icariin and Its Metabolites on GPCR Regulation and MK-801-Induced Schizophrenia-Like Behaviors in Mice.

Icariin, a major bioactive compound found in the Epimedium genus, has been reported to exert protective effects against neurodegenerative disorders. In the current study, we aimed to investigate the regulatory effect of icariin and its active metabolites (icariside II and icaritin) against prime G-protein-coupled receptor targets, considering their association with neuronal disorders. Icariside II exhibited selective agonist activity towards the dopamine D3 receptor (D3R), with half-maximal effective concentrations of 13.29 µM. Additionally, they effectively inhibited the specific binding of radioligands to D3R. Molecular docking analysis revealed that icariside II potentially exerts its agonistic effect through hydrogen-bonding interaction with Asp110 of the D3R, accompanied by negative binding energy. Conversely, icaritin demonstrated selective antagonist effects on the muscarinic acetylcholine M2 receptor (M2R). Radioligand binding assay and molecular docking analysis identified icaritin as an orthosteric ligand for M2R. Furthermore, all three compounds, icariin and its two metabolites, successfully mitigated MK-801-induced schizophrenia-like symptoms, including deficits in prepulse inhibition and social interaction, in mice. In summary, these findings highlight the potential of icariin and its metabolites as promising lead structures for the discovery of new drugs targeting cognitive and neurodegenerative disorders.

The protective effect of N-acetylcysteine against MK-801-induced neurodegeneration in mice.

BACKGROUND: Neurological disorders result in not only a decline in the quality of life of patients but also a global economic burden. Therefore, protective medicine becomes more important for society. MK-801 is a chemical agent used to understand the etiology of behavioral disorders and brain degeneration in animal models. This study aims to determine whether N-acetylcysteine (NAC) is useful to treat brain degeneration caused by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. METHODS AND RESULTS: Four groups were formed by dividing 24 male BALB/c mice into groups of six. The control group was given a saline solution (10 ml/kg-i.p.). MK-801 (1 mg/kg-i.p.) was given alone to one group, and it was given with NAC (100 mg/kg-i.p.) to another group, while the last group was given only NAC (100 mg/kg-i.p.). The administration of drugs lasted for fourteen days. After the behavioral tests (open field and elevated plus-maze), all animals were euthanised, and brain tissues were collected for real-time PCR, TAS-TOS analysis, hematoxylin-eosin, Kluver-Barrera, and TUNEL staining. In the MK-801 group, besides nuclear shrinkage in neurons, glial cell infiltration, vacuolization in cortical neurons, white matter damage, and apoptosis were observed. CONCLUSION: In the mice given NAC as a protective agent, it was observed that behavioral problems improved, antioxidant levels increased, and nuclear shrinkage, glial cell infiltration, vacuolization in neurons, and white matter degeneration were prevented. Moreover, MBP expression increased, and the number of TUNEL-positive cells significantly decreased. As a result, it was observed that NAC may have a protective effect against brain degeneration.

Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen.

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.