Search Results (63)

In animal models, ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, induces schizophrenia-like symptoms, such as positive and negative symptoms, as well as cognitive deficits. In the present study, we evaluated the behavioral responses and the number of EODs (electric organ discharges) of the weakly electric fish Gnathonemus petersii using the novel object recognition task (NORT). We aimed to investigate whether pharmacological modulation of the glutamatergic system would impair cognitive functions by administering the NMDA receptor antagonist ketamine, and whether these impairments could be suppressed by the administration of typical (first-generation) and atypical (second-generation) antipsychotics—clozapine and haloperidol, respectively. G. petersii preferred the familiar object over the novel object in the NORT paradigm. Although no significant differences were observed when exploring the two identical objects during the training session, the fish spent less time, moved a shorter distance, and emitted fewer EODs in the testing phase with the novel object. No direct relationship was detected between the EODs and behavioral responses to the administration of ketamine and typical antipsychotics. Ketamine administered with atypical antipsychotic clozapine disrupted the perception of the original object, where one of the objects was preferred. In the novel object trial, the time spent on the original and new objects was attenuated to the same level. Full article

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays an important role in transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations in the glutamatergic signaling pathway are now accepted as a central element in Alzheimer’s disease (AD) pathophysiology. One of the most prevalent types of dementia in older adults is AD, a progressive neurodegenerative illness brought on by a persistent decline in cognitive function. Since AD has been shown to be multifactorial, a variety of pharmaceutical targets may be used to treat the condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists and acetylcholinesterase inhibitors (AChEIs) are two drug classes that the Food and Drug Administration has authorized for the treatment of AD. The AChEIs approved to treat AD are galantamine, donepezil, and rivastigmine. However, memantine is the only non-competitive NMDAR antagonist that has been authorized for the treatment of AD. This review aims to outline the involvement of glutamate (GLU) at the molecular level and the signaling pathways that are associated with AD to demonstrate the drug target therapeutic potential of glutamate and its receptor. We will also consider the opinion of the leading authorities working in this area, the drawback of the existing therapeutic strategies, and the direction for the further investigation. Full article

Background: N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. Methods: The purpose of the present review is to provide a detailed description of NMDARs by addressing their molecular structures, activation mechanisms, and physiological roles in the mammalian brain. In the second part, their role in various neuropsychiatric disorders including stroke, epilepsy, anti-NMDA encephalitis, Alzheimer’s and Huntington’s diseases, schizophrenia, depression, neuropathic pain, opioid-induced tolerance, and hyperalgesia will be covered. Results: Finally, through a careful exploration of the main non-competitive NMDARs antagonists (channel-blockers). Conclusion: We discuss the strengths and limitations of the various molecular structures developed for diagnostic or therapeutic purposes. Full article

Memantine, a non-competitive NMDA receptor antagonist, is used to treat Alzheimer’s disease. Therefore, loading memantine in nanoparticles (NPs) could be an essential tool to improve the treatment effectiveness while reducing drug toxicity. Even though some approaches have been described to quantify memantine, none reported optimized methods using high-performance liquid chromatography resorting to ultraviolet detection (UV–HPLC) to determine encapsulation in NPs. The present research developed a HPLC method using pre-column derivatization for quantitatively analyzing memantine hydrochloride in NPs. Memantine was derivatized using 9-fluorenylmethyl chloroformate (FMOC). The developed method was fully validated regarding suitability, specificity, linearity, sensitivity, precision, accuracy, and robustness according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The retention time of memantine was 11.393 ± 0.003 min, with a mean recovery of 92.9 ± 3.7%. The new chromatographic method was validated and found to respond linearly over 5–140 μg/mL, with a high coefficient of determination. Intraday precision lay between 3.6% and 4.6%, and interday precision between 4.2% and 9.3%. The stability of memantine was also tested at 4 °C and −20 °C, and no signs of decay were found for up to 6 months. The new method was properly validated and proved simple, sensitive, specific, accurate, and precise for determining memantine encapsulation efficiency in lipid NPs. Greenness was evaluated, presenting a final score of 0.45. In the future, this methodology could also be applied to quantify memantine in different nanoformulations. Full article

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood–brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators. Full article

New Psychoactive Substances (NPS) are modifying the drug scenario worldwide and have become a public health concern because of their toxicological profiles and their harmful physical/psychological effects. 3-Methoxy-Phencyclidine (3-MeO-PCP), a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors, belongs to the phencyclidine-like subfamily of arylcyclohexylamines and has gained attention for its toxic, sometimes fatal, effects. Despite several cases of intoxication and death reported in the literature, little is known about substance-induced psychotic disorders (SIP) and potential cognitive impairment following 3-MeO-PCP intake. This literature review aimed to summarize available evidence about 3-MeO-PCP mechanisms of action and physical and psychotropic effects and to spread preliminary findings about persistent psychotic symptoms and impaired cognitive functioning. Additionally, the case of an SIP is reported in a 29-year-old man with small oral intakes of 3-MeO-PCP over two weeks until a high dose ingestion. Psychometric and neuropsychological assessment and brain [¹⁸F]-fluorodeoxyglucose positron emission tomography integrated with computed tomography were used to support clinical description. Identifying and addressing the characteristic clinical features and neural substrates of NPS-induced psychoses might help clinicians with a more precise differentiation from other psychotic disorders. Although further studies are required, phenotyping the cognitive profile of NPS users might provide targets for tailored therapeutic approaches. Full article

Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4⁺ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes’ mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats. Full article

Ketamine as an old–new drug has a variety of clinical implications. In the last 30 years, ketamine has become popular for acute use in humans. Ketamine in standard doses is principally utilized for the induction and maintenance of surgical procedures. Besides its use in anesthesia and analgesia, recent studies have shown that ketamine has found a place in the treatment of asthma, epilepsy, depression, bipolar affective disorders, alcohol and heroin addiction. Ketamine primarily functions as a noncompetitive antagonist targeting the N-methyl-D-aspartate (NMDA) receptor, but its mechanism of action is complex. It is generally regarded as safe, with low doses and short-term use typically not leading to significant adverse effects. Also, ketamine is known as a powerful psychostimulant. During the past decade, ketamine has been one of the commonly abused drugs. Full article

Background: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. Methods: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague–Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. Results: In Sprague–Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. Conclusions: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors. Full article

Memantine is an FDA-approved, non-competitive NMDA-receptor antagonist that has been shown to have mitochondrial protective effects, improve cell viability and enhance clearance of Aβ₄₂ peptide. Currently, there are uncertainties regarding the precise molecular targets as well as the most favourable treatment concentrations of memantine. Here, we made use of an imaging-based approach to investigate the concentration-dependent effects of memantine on mitochondrial fission and fusion dynamics, autophagy and mitochondrial quality control using a neuronal model of CCCP-induced mitochondrial injury so as to better unpack how memantine aids in promoting neuronal health. GT1-7 murine hypothalamic cells were cultured under standard conditions, treated with a relatively high and low concentration (100 µM and 50 µM) of memantine for 48 h. Images were acquired using a Zeiss 780 PS1 platform. Utilising the mitochondrial event localiser (MEL), we demonstrated clear concentration-dependent effects of memantine causing a protective response to mitochondrial injury. Both concentrations maintained the mitochondrial network volume whilst the low concentration caused an increase in mitochondrial number as well as increased fission and fusion events following CCCP-induced injury. Additionally, we made use of a customised Python-based image processing and analysis pipeline to quantitatively assess memantine-dependent changes in the autophagosomal and lysosomal compartments. Our results revealed that memantine elicits a differential, concentration-dependent effect on autophagy pathway intermediates. Intriguingly, low but not high concentrations of memantine lead to the induction of mitophagy. Taken together, our findings have shown that memantine is able to protect the mitochondrial network by preserving its volume upon mitochondrial injury with high concentrations of memantine inducing macroautophagy, whereas low concentrations lead to the induction of mitophagy. Full article

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus. Full article

Tandem of P domains in a weak inwardly rectifying K⁺ channel (TWIK)-related acid sensitive K⁺-1 channel (TASK-1) is activated under extracellular alkaline conditions (pH 7.2–8.2), which are upregulated in astrocytes (particularly in the CA1 region) of the hippocampi of patients with temporal lobe epilepsy and chronic epilepsy rats. Perampanel (PER) is a non-competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) antagonist used for the treatment of focal seizures and primary generalized tonic–clonic seizures. Since AMPAR activation leads to extracellular alkaline shifts, it is likely that the responsiveness to PER in the epileptic hippocampus may be relevant to astroglial TASK-1 regulation, which has been unreported. In the present study, we found that PER ameliorated astroglial TASK-1 upregulation in responders (whose seizure activities were responsive to PER), but not non-responders (whose seizure activities were not responsive to PER), in chronic epilepsy rats. ML365 (a selective TASK-1 inhibitor) diminished astroglial TASK-1 expression and seizure duration in non-responders to PER. ML365 co-treatment with PER decreased spontaneous seizure activities in non-responders to PER. These findings suggest that deregulation of astroglial TASK-1 upregulation may participate in the responsiveness to PER, and that this may be a potential target to improve the efficacies of PER. Full article

While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence. Ketamine is derived from phencyclidine and acts as a noncompetitive antagonist and allosteric modulator of N-methyl-D-aspartate receptors. Ketamine has been used to treat a variety of psychiatric disorders, with the most notable being treatment-resistant depression. With the rise of at-home ketamine treatment companies, the safety of unsupervised administration remains under evaluation. A study with ketamine and a ketamine-like medication, rapasitnel, showed that those who were given ketamine experienced more sleepiness and had decreased self-reported motivation and confidence in their driving abilities. Moreover, there seem to be significant differences in the acute versus persistent effects of ketamine, as well as the anesthetic versus subanesthetic doses, both in terms of effects and outcomes. These divergent effects complicate the clinical uses of ketamine, specifically involving driving, drowsiness, and cognitive abilities. This review aims to describe not only the various clinical uses of ketamine but also the potentially detrimental effects of driving under the influence, which should be understood to help with counseling the patients who use these substances, both for their well-being and to protect public safety. Full article

(1) Background: Epilepsy is a frequent comorbidity in patients with brain tumors, in whom seizures are often drug-resistant. Current evidence suggests that excess of glutamatergic activity in the tumor microenvironment may favor epileptogenesis, but also tumor growth and invasiveness. The selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel (PER) was demonstrated to be efficacious and well-tolerated in patients with focal seizures. Moreover, preclinical in vitro studies suggested a potential anti-tumor activity of this drug. In this systematic review, the clinical evidence on the efficacy and tolerability of PER in brain tumor-related epilepsy (BTRE) is summarized. (2) Methods: Five databases and two clinical trial registries were searched from inception to December 2022. (3) Results: Seven studies and six clinical trials were included. Sample size ranged from 8 to 36 patients, who received add-on PER (mean dosage from 4 to 7 mg/day) for BTRE. After a 6–12 month follow-up, the responder rate (% of patients achieving seizure freedom or reduction ≥ 50% of seizure frequency) ranged from 75% to 95%, with a seizure freedom rate of up to 94%. Regarding tolerability, 11–52% of patients experienced non-severe adverse effects (most frequent: dizziness, vertigo, anxiety, irritability). The retention rate ranged from 56% to 83%. However, only up to 12.5% of patients discontinued the drug because of the adverse events. (4) Conclusions: PER seems to be efficacious, safe, and well-tolerated in patients with BTRE. Further randomized studies should be conducted in more homogeneous and larger populations, also evaluating the effect of PER on tumor progression, overall survival, and progression-free survival. Full article

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward ‘non-NMDA’ (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds. Full article