Non-competitive Antagonist Research Articles

Atypical antipsychotic drug olanzapine inhibits 5-HT3 receptor-mediated currents by allosteric and non-competitive mechanisms.

Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)2A receptors, recent evidence suggests that olanzapine also inhibits 5-HT3 receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT3 receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells. Results of this study indicated that olanzapine could act as a non-competitive antagonist of the 5-HT3 receptor, exhibiting concentration-dependent inhibition of ion currents. Moreover, olanzapine facilitated both deactivation and desensitization kinetics, accelerating decay of 5-HT3 receptor-mediated currents. Recovery from desensitization was significantly delayed by olanzapine, whereas recovery from deactivation was largely unaffected by it. Current-voltage relationship analysis revealed that olanzapine reduced the amplitude of 5-HT3 receptor-mediated currents across all holding potentials without altering reversal potential, suggesting a voltage-independent inhibition. Furthermore, olanzapine exhibited use-dependent inhibition, with a greater reduction in current observed during more frequent 5-HT application. These findings provide novel insights into a non-competitive and allosteric inhibition of 5-HT3 receptors by olanzapine, contributing to a deeper understanding of its pharmacological profile in neuropsychiatric and gastrointestinal conditions where serotonergic neurotransmission is implicated.

Memantine-induced functional rewiring of the glutamate synapse in the striatum of dopamine transporter knockout rats.

Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT-/-) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view. The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT-/- rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg-1). Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DAT-/-rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT-/- rats, thus restoring functional LTD. A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.

Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

Optimal Continuous Administration of Drugs Exhibiting Tolerance: A Modeling Study for Linear One Compartment Pharmacokinetics

For many drugs exhibiting tolerance, it is not possible to maintain efficacy without intermittently halting administration, enabling the body to restore its sensitivity to the drug. Periodic delivery is thus called for. Here we calculate the optimal periodic delivery protocol to maintain efficacy for the largest fraction of time. Calculations are based on a model assuming that tolerance is due to the buildup of a noncompetitive antagonist. The optimal periodic control starts with a bolus of drug followed by a continuously increasing input rate, with input ultimately halted to allow washout of the antagonist. Variables to be optimized are size of the bolus, duration and “waveform” of the continuous input, and duration of the shutoff phase. This work, which assumes a “hard” threshold for drug efficacy, builds on previous papers in which a “fuzzy” threshold was used for computational convenience. Consequences of varying model parameters are explored.

Esketamine Provides Neuroprotection After Intracerebral Hemorrhage in Mice via the NTF3/PI3K/AKT Pathway.

Esketamine (ESK), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, modulates neurotransmitter signaling in the central nervous system. However, the specific mechanisms and therapeutic potential of ESK for intracerebral hemorrhage (ICH) remain unclear. This study aimed to investigate whether ESK promotes nerve repair and improves neurological outcomes in an experimental model of ICH. ICH was induced in mice via collagenase injection into the striatum. Body weight, neurological impairment, and behavioral changes were assessed. ESK administration significantly improved several indicators of ICH. Comprehensive RNA transcriptome sequencing and network pharmacology analyses identified neurotrophin-3 (NTF3) and the PI3K/AKT signaling pathway as targets for ESK treatment. Western blotting and immunofluorescence detected the protein expression levels and cellular localization of NTF3. After 28 days of adeno-associated virus infection in the mouse striatum, ESK treatment significantly enhanced neuroprotection, indicating the crucial role of NTF3 in ESK-mediated neuroprotection in ICH mice. Inhibition of the PI3K/AKT pathway using the PI3K-specific inhibitor LY294002 significantly attenuated the therapeutic effects of ESK, suggesting that this pathway is involved in ESK-mediated neurorepair in ICH mice. ESK treatment significantly improved functional outcomes and demonstrated neuroprotective effects in animal models of ICH. NTF3/PI3K/AKT pathway activation by ESK indicates its therapeutic potential in the treatment of ICH.

Ketamine differentially affects implicit and explicit memory processes in rats.

Ketamine, a non-competitive NMDA receptor antagonist, produces antidepressant effects at subanesthetic doses. The therapeutic effect, however, is often accompanied by cognitive side effects, including memory impairments. Yet, the specific effects of ketamine on different processes of implicit and explicit memory remain to be elucidated. We examined the effect of an antidepressant dose of ketamine (10mg/kg, IP) on the encoding, retrieval, and modulation processes of fear memory and spatial memory in adult Wistar rats. Ketamine was administered before the fear acquisition, retrieval, or extinction procedures in a Pavlovian fear conditioning task. In another set of experiments, it was administered before the training, probe trial, or reversal training phases of the Morris Water Maze (MWM). The antidepressant dose of ketamine partially impaired fear extinction when administered before the acquisition or retrieval. In contrast, it facilitated memory modulation and decreased the escape latency in the first day of reversal training in the MWM when administered before the training or reversal training sessions. Encoding or retrieval performance in either type of memory was not affected. These findings show that ketamine does not impair the acquisition or retrieval processes of cued fear or spatial memory; but exerts differential effects on memory modulation of these implicit and explicit memory paradigms, by disrupting fear extinction and facilitating reversal spatial learning.

Haloperidol, a typical antipsychotic, inhibits 5-HT3 receptormediated currents in NCB-20 cells: a whole-cell patch-clamp study.

Haloperidol is a typical antipsychotic drug effective in alleviating positive symptoms of schizophrenia by blocking dopamine receptor 2 (DR2). However, it is also known to produce neuropsychiatric effects by acting on various targets other than DR. In this study, we investigated effect of haloperidol on function of 5-hydroxytryptamine (5-HT)3 receptor, a ligand-gated ion channel belonging to the serotonin receptor family using the whole-cell voltage clamp technique and NCB20 neuroblastoma cells. When co-applied with 5-HT, haloperidol inhibited 5-HT3 receptormediated currents in a concentration-dependent manner. A reduction in maximal effect (Emax) and an increase in EC50 observed during co-application indicated that haloperidol could act as a non-competitive antagonist of 5-HT3 receptors. Haloperidol inhibited the activation of 5-HT3 receptor, while also accelerating their deactivation and desensitization. The inhibitory effect of haloperidol showed no significant difference between pre- and co-application. Haloperidol did not alter the reversal potential of 5-HT3 receptor currents. Furthermore, haloperidol did not affect recovery from deactivation or desensitization of 5-HT3 receptors. It did not show a use-dependent inhibition either. These findings suggest that haloperidol can exert its inhibitory effect on 5-HT3 receptors by allosterically preventing opening of ion channels. This mechanistic insight enhances our understanding of relationships between 5-HT3 receptors and pharmacological actions of antipsychotics.

Sugammadex for our little ones: a brief narrative review.

Sugammadex, the first noncompetitive antagonist developed for the reversal of neuromuscular blockade (NMB), is one of the few drugs that has revolutionized anesthetic practice. However, the use of sugammadex for children between the ages of 2 and 17 years has only recently been approved and is currently not approved for children under the age of 2 years. Although the precision and reliability of reversal of NMB with sugammadex are of great benefit in pediatric anesthesia, several important questions remain regarding its use in our youngest patients. In this brief narrative review, we aim to provide an overview of the key considerations and potential challenges that anesthesiologists often face when using sugammadex in pediatric patients.

The Impact of Local Ketamine on Spatial Cognition Through Dopamine

The dopamine system plays a crucial role in maintaining spatial cognitive functions. Ketamine, a non-competitive NMDA receptor antagonist, indirectly affects dopamine release and function by modulating glutamatergic neuronal activity, leading to spatial cognitive impairments. This study aims to explore the specific mechanisms through which local ketamine administration affects spatial cognition. By injecting ketamine into the hippocampus of mice and combining behavioral experiments with brain tissue analysis, we found that ketamine-induced dopamine damage significantly impairs the mice’s spatial orientation abilities. This discovery offers new insights into the negative impact of ketamine addiction on cognitive function.

Effectiveness and safety of Perampanel in refractory status epilepticus: a case series.

Perampanel is a selective non-competitive antagonist of AMPA receptors, and the first agent of this class to become available for the treatment of epilepsy. It could be a useful tool for treatment of refractory status epilepticus (RSE). We describe a series of eight RSE cases treated with Perampanel. Perampanel was successful in terminating SE in all the described cases. Only in one patient a severe psychomotor agitation occurred, but without needing PER discontinuation. No other adverse events were observed. Our case series of eight patients, albeit small, broadens the clinical experiences on the efficacy and safety of PER as a treatment for RSE. It may also support the early use of PER, considering the role of AMPA receptors in sustaining epileptic firing in SE. Further studies are warranted to clarify the potential of Perampanel in the treatment of status epilepticus and, in particular, in RSE.

Design, Synthesis, and Study of Novel Memantine Schiff Base Derivatives Against Targeted Enzymes in Alzheimer’s Disease

Introduction: According to WHO, Alzheimer’s disease was estimated at 74.4 million cases in 2023, which will increase by 152.8 million cases in 2050. The therapeutic options available in the market for the treatment of AD are only capable of reducing the symptoms of dementia but not preventing progressive degeneration. Memantine is a non-competitive NMDAR antagonist used for the treatment of patients with moderate-to-severe AD, but it has a high toxicity profile. To counter this, the Memantine Schiff base derivatives were designed as simple and lowtoxicity compounds. Materials and Methods: Molecular docking was performed against the targeted enzymes Acetylcholinesterase and Butyrylcholinesterase using AUTODOCK 1.5.7 software. A series of novel Memantine derivatives of Schiff base were synthesized by condensing Memantine with various aryl aldehydes and screened for their invitro-cholinesterase inhibitory activity towards Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) by Ellman’s method. Results and Discussion: Among the designed compounds, compounds LMV and LMC showed maximum binding scores of -10.35 kcal/mol and -10.12 kcal/mol, respectively, than the standard Donepezil (-8.78 kcal/mol) against Acetylcholinesterase. The compounds LMONB and LMDMB produced significant binding scores of -9.31 kcal/mol and -9.11 kcal/mol, respectively, compared to the standard Donepezil (-7.57 kcal/mol) against Butyrylcholinesterase. Also, compounds LMV (30.9 ± 2.13 μM) and LMDMB (13.51 ± 1.12 μM) showed potent inhibitory activity against the AChE and BChE. These compounds possess drug-like characteristics and are also capable of crossing the Blood Brain Barrier (BBB). Conclusion: The studied compounds LMV and LMDMB, being non-toxic, obey Lipinski’s rule of 5 and are potential inhibitors against targeted enzymes, which may be promising clinical candidates for treating Alzheimer’s disease.

Ketamine modulates the exploratory dynamics and homebase-related behaviors of adult zebrafish

Anxiety can be a protective emotion when animals face aversive conditions, but is commonly associated with various neuropsychiatric disorders when pathologically exacerbated. Drug repurposing has emerged as a valuable strategy based on utilizing the existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the glutamate N-methyl-d-aspartate (NMDA) receptor, and shows potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and their locomotion-, exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that acute ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips, suggest anxiolytic-like effects. Collectively, our findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, and corroborate the utility of homebase-related measurements to evaluate the behavioral dynamics in zebrafish models.

Two distinct enriched housings differentially ameliorate object and place recognition deficits in a rat model of schizophrenia

Schizophrenia is a psychiatric disorder characterized by cognitive dysfunctions. These dysfunctions significantly impact the daily lives of schizophrenic patients, yet effective interventions remain scarce. In this study, we explored the effects of two enriched housing types—cognitive and physical—on cognitive dysfunctions in a rat model of schizophrenia. Male neonatal Wistar-Imamichi rats were administered MK-801, a noncompetitive NMDAR antagonist, twice daily from postnatal day (PND) 7 to PND 20. Physical enrichment ameliorated memory deficits in both object and place recognition tests, while cognitive enrichment primarily improved object recognition performance. Our findings suggest that exercise therapy could be a potential approach to address cognitive dysfunctions in schizophrenia patients.

Recreational ketamine use and its impact on health

Ketamine, also known as 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone, is a dissociative anesthetic that has gained popularity as a recreational substance among young people, especially in nightclubs and at parties. It acts as a noncompetitive NMDA receptor antagonist, inducing a dissociative state that manifests as catalepsy, unconsciousness and amnesia. Recreational use of ketamine and the number of illicit seizures of ketamine have increased in recent years, prompting a review of current evidence on its toxicity. Recreational ketamine use is associated with a number of toxic effects, both acute and chronic. Predominant among the acute effects are psychotic symptoms, hallucinations and aggression, which can lead to serious injuries. Chronic ketamine use leads to intractable urological problems and neuropsychiatric problems, Long-term effects also include gastrointestinal problems such as abdominal pain and liver function abnormalities. This review summarizes current evidences on the acute and chronic ketamine toxicity associated with its recreational use.

Unraveling the Interplay of 5-hydroxytryptamine-3 and N-methyl-d-aspartate Receptors in Seizure Susceptibility

Abstract Background Epilepsy, a prevalent neurological disorder characterized by recurrent seizures, presents significant challenges in treatment and management. This study aimed to evaluate the effect of tropisetron, a selective 5-HT3 receptor antagonist on pentylenetetrazole (PTZ) – induced seizure in mice by exploring the potential role of the NMDA receptor and inflammatory responses. Methods For this purpose, seizures were induced by intravenous PTZ infusion. Tropisetron at 1-, 2-, 3-, 5-, 10- mg/kg were administered intraperitoneally 30 minutes before PTZ. To evaluate probable role of NMDA signaling, selective NMDAR antagonists, ketamine and MK-801, were injected 15 minutes before tropisetron. Also, TNF-α level of hippocampus were measured following administration of mentioned drugs in mice. Results Our results demonstrate that tropisetron displayed a dose-dependent impact on seizure threshold, with certain doses (5 and 10 mg/kg) exhibiting anticonvulsant properties. In addition, the noncompetitive NMDAR antagonists, ketamine (1 mg/kg) and MK-801 (0.5 mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of tropisetron (3 mg/kg). Also, tropisetron led to a reduction in hippocampal TNF-α levels, indicating its anti-inflammatory potential independent of 5-HT receptor activity. Conclusion In conclusion, we demonstrated that the anticonvulsant effect of tropisetron is mediated by the inhibition of NMDA receptors and a decline in hippocampal TNF-α level. These findings highlight a potential connection between 5-HT3 and NMDA receptors in the pharmacological treatment of inflammatory diseases, such as seizure, warranting further investigation into their combined therapeutic effects.

Development and Validation of a Simple UV-HPLC Method to Quantify the Memantine Drug Used in Alzheimer's Treatment.

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.

Structural basis of TRPV1 inhibition by SAF312 and cholesterol

Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312’s inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies.

Blood Vessels

Abstract: One of the primary target tissues for inflammatory and allergy mediators is the blood vessel, and cytokines have a variety of impacts on it. We describe the usefulness of isolated blood vessels immersed in organ baths as a valuable source of pharmacological data. Contractility assays provide strong potency and selectivity data on agonists, partial agonists, and competitive or noncompetitive antagonists; however, their use in the bioassay of vasoactive drugs is gradually being replaced by more advanced analytical techniques. The human umbilical vein, for instance, has been widely utilized to identify bradykinin B2 receptor ligands. Isolated segments of vascular tissue are highly reactive living tissues, particularly in terms of regulating gene products associated with inflammation (e.g., kinin B1 receptor). The venule’s extremely thin walls have the potential to burst due to their high volume. Venules allow blood to move into larger veins. Both veins and arteries have three layers in their walls. On the other hand, venous pressure is modest. Veins are less elastic and have thin walls, allowing them to maintain a high blood circulation rate. The venous system’s high capacitance enables it to store a significant amount of blood at comparatively low pressures, containing around 75% of the circulating blood at any given time. The veins’ one-way valves permit blood to move forward toward the heart through muscle contractions.

Administration of low dose intranasal ketamine exerts a neuroprotective effect on whole brain irradiation injury model in wistar rats.

Exposure to ionizing radiation leads to oxidative stress and neuroinflammation, resulting in neurocognitive impairments. Adverse effects are also associated with glutamate-induced excitotoxicity due to alterations in the composition of glutamate receptors. Ketamine, which is a noncompetitive NMDA glutamate receptor antagonist, has been stated to exert an impact on glutamatergic receptors. This study aims to reveal the possible alleviating or preventive effects of ketamine, which maintains glutamate homeostasis and decreases neurodegeneration, in a radiation-induced neurotoxicity model. Twenty-one female Wistar Queryrats were included in the study and 14 of these underwent whole brain irradiation (IR) with a 20 Gray single dose. Animals were allocated into three groups. Group 1: Normal control; Group 2: Placebo / IR + Saline; Group 3: IR + Ketamine. Ketamine was administered in addition to IR to rats in Group 3. The one-way ANOVA statistical test was used to compare groups. The value of p < 0.05 was considered statistically significant. When administered in addition to irradiation, ketamine treatment significantly increased scores in the three-chamber sociability test, open field test, and passive avoidance learning test. It also raised neuron counts in the hippocampal CA1 and CA3 regions as well as in Purkinje cells, and enhanced levels of brain-derived neurotrophic factor and tyrosine receptor kinase-B. Furthermore, ketamine administration resulted in decreased levels of glial fibrillary acidic protein, malondialdehyde, and tumor necrosis factor-alpha, indicating a reduction in neuroinflammation and oxidative stress. Ketamine exerted a significant protective impact on radiation-induced neurocognitive impairments and enhanced social-memory capacity by reducing neuronal loss, oxidative stress, and neuroinflammation. Our findings suggest that ketamine is beneficial in the treatment or prevention of neurodegeneration via the regulation of the BDNF/TrkB signaling pathway besides decreasing neuroinflammation and blocking NMDA receptors.

NMDA Receptors and Indices of Energy Metabolism in Erythrocytes: Missing Link to the Assessment of Efficiency of Oxygen Transport in Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in patients with severe liver dysfunction and/or portocaval shunting. Despite more than a century of research into the relationship between liver damage and development of encephalopathy, pathogenetic mechanisms of hepatic encephalopathy have not yet been fully elucidated. It is generally recognized, however, that the main trigger of neurologic complications in hepatic encephalopathy is the neurotoxin ammonia/ammonium, concentration of which in the blood increases to toxic levels (hyperammonemia), when detoxification function of the liver is impaired. Freely penetrating into brain cells and affecting NMDA-receptor-mediated signaling, ammonia triggers a pathological cascade leading to the sharp inhibition of aerobic glucose metabolism, oxidative stress, brain hypoperfusion, nerve cell damage, and formation of neurological deficits. Brain hypoperfusion, in turn, could be due to the impaired oxygen transport function of erythrocytes, because of the disturbed energy metabolism that occurs in the membranes and inside erythrocytes and controls affinity of hemoglobin for oxygen, which determines the degree of oxygenation of blood and tissues. In our recent study, this causal relationship was confirmed and novel ammonium-induced pro-oxidant effect mediated by excessive activation of NMDA receptors leading to impaired oxygen transport function of erythrocytes was revealed. For a more complete evaluation of "erythrocytic" factors that diminish brain oxygenation and lead to encephalopathy, in this study, activity of the enzymes and concentration of metabolites of glycolysis and Rapoport-Lubering shunt, as well as morphological characteristics of erythrocytes from the rats with acute hyperammoniemia were determined. To elucidate the role of NMDA receptors in the above processes, MK-801, a non-competitive receptor antagonist, was used. Based on the obtained results it can be concluded that it is necessary to consider ammonium-induced morphofunctional disorders of erythrocytes and hemoglobinemia which can occur as a result of alterations in highly integrated networks of metabolic pathways may act as an additional systemic "erythrocytic" pathogenetic factor to prevent the onset and progression of cerebral hypoperfusion in hepatic encephalopathy accompanied by hyperammonemia.