Recognizing the opponent: The consolidation of long-term social memory in zebrafish males.

Recognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow for avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 h later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and fight again 48 or 72 h later, they resolve the second encounter with lower levels of aggression. However, if opponents were exposed to MK-801 (NMDA receptor antagonist) immediately after the first encounter, they solved the second one with the same levels of aggression: that is, no reduction in aggressive behaviors was observed. These amnesic effect suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.

Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis.

Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = - 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters, mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indications of TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, and impact on cognition. An overview of the drug's origins, pharmacology, and standard treatment regimen are provided. The outcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlined to demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative to ketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD, propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, including ketamine, esketamine, treatment-resistant depression, and biomarkers, using automation tools along with selective search engine results. After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14, a novel N-methyl-d-aspartate receptor antagonist, in rats by liquid chromatography-tandem mass spectrometry.

To circumvent the limitations of current antidepressants, WJ-14, a novel N-methyl-d-aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14 in rats, a rapid and sensitive liquid chromatography-tandem mass spectrometry-based analytical method was developed and validated for the separation and detection of WJ-14 in both plasma and tissue samples. After oral administration, WJ-14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax ) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half-life (t1/2 ) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ-14 was extensively distributed in the main tissues of rats, and massive amounts of WJ-14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ-14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ-14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid-onset antidepressant candidate. In addition, WJ-14 likely exhibited a non-linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ-14.

Necroptosis involved in sevoflurane-induced cognitive dysfunction in aged mice by activating NMDA receptors increasing intracellular calcium.

Perioperative neurocognitive disorders are a common surgical and postanesthesia complication. Necroptosis contributes to the emergence of various neurological disorders. We conjecture that cognitive impairment is associated with necroptosis of hippocampal neurons, which is mediated by NMDA receptors leading to cytoplasmic calcium imbalance. C57BL/6 J male mice ( 18 months) were randomly divided into the C ( control group), S ( sevoflurane group), S+M ( sevoflurane plus the NMDA receptor antagonist memantine group) and S+N ( sevoflurane plus necrostatin-1) group. We exposed the mice to 3% sevoflurane for 2 h a day for three consecutive days in the S, S+M and S+N groups. Memantine ( 20 mg/kg) or Nec-1 ( 10 mg/kg) was injected intraperitoneally 1 h before sevoflurane anesthesia in the S+M or S+N group. We used the animal behavior tests to evaluate the cognitive function. Pathological damage, the rate of necroptosis, [Ca2+]i, and the expression of necroptosis-related proteins were evaluated. The cognitive function tests, pathological damage, the rate of necroptosis, the expression of necroptosis-related proteins, NMDAR2A and NMDAR2B were significantly different in the S group ( P < 0.05). Alleviated pathological damage, decreased the rate of necroptosis and down-regulated the expression of necroptosis-related proteins occurred in the S+M and S+N group ( P < 0.05). The lower elevated [Ca2+]i, expression of NMDAR2A and NMDAR2B were found in the S+M group. Our findings highlighted sevoflurane-induced cognitive dysfunction is associated with an imbalance in cytoplasmic calcium homeostasis by activating NMDA receptors, which causes hippocampus neurons to undergo necroptosis and ultimately affects cognitive performance in aged mice.

Attenuation of Vanadium-Induced Neurotoxicity in Rat Hippocampal Slices (In Vitro) and Mice (In Vivo) by ZA-II-05, a Novel NMDA-Receptor Antagonist.

Exposure to heavy metals, such as vanadium, poses an ongoing environmental and health threat, heightening the risk of neurodegenerative disorders. While several compounds have shown promise in mitigating vanadium toxicity, their efficacy is limited. Effective strategies involve targeting specific subunits of the NMDA receptor, a glutamate receptor linked to neurodegenerative conditions. The potential neuroprotective effects of ZA-II-05, an NMDA receptor antagonist, against vanadium-induced neurotoxicity were explored in this study. Organotypic rat hippocampal slices, and live mice, were used as models to comprehensively evaluate the compound's impact. Targeted in vivo fluorescence analyses of the hippocampal slices using propidium iodide as a marker for cell death was utilized. The in vivo study involved five dams, each with eight pups, which were randomly assigned to five experimental groups (n = 8 pups). After administering treatments intraperitoneally over six months, various brain regions were assessed for neuropathologies using different immunohistochemical markers. High fluorescence intensity was observed in the hippocampal slices treated with vanadium, signifying cell death. Vanadium-exposed mice exhibited demyelination, microgliosis, and neuronal cell loss. Significantly, treatment with ZA-II-05 resulted in reduced cellular death in the rat hippocampal slices and preserved cellular integrity and morphological architecture in different anatomical regions, suggesting its potential in countering vanadium-induced neurotoxicity.

Classics in Chemical Neuroscience: Dextromethorphan (DXM).

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N-methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.

Investigating the Robustness of a Rodent "Double Hit" (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review.

Schizophrenia is a debilitating psychiatric disorder comprising positive, negative, and cognitive impairments. Most of the animal models developed to understand the neurobiology and mechanism of schizophrenia do not produce all the symptoms of the disease. Therefore, researchers need to develop new animal models with greater translational reliability, and the ability to produce most if not all symptoms of schizophrenia. This review aimed to evaluate the effectiveness of the rodent "double hit" (post-weaning social isolation and N-methyl-D-aspartate (NMDA) receptor antagonist) model to produce symptoms of schizophrenia. This systematic review was developed according to the 2020 PRISMA guidelines and checklist. The MEDLINE (PubMed) and Ebscohost databases were used to search for studies. The systematic review is based on quantitative animal studies. Studies in languages other than English that could be translated sufficiently using Google translate were also included. Data extraction was performed individually by two independent reviewers and discrepancies between them were resolved by a third reviewer. SYRCLE's risk-of-bias tool was used to test the quality and biases of included studies. Our primary search yielded a total of 47 articles, through different study selection processes. Seventeen articles met the inclusion criteria for this systematic review. Ten of the seventeen studies found that the "double hit" model was more effective in developing various symptoms of schizophrenia. Most studies showed that the "double hit" model is robust and capable of inducing cognitive impairments and positive symptoms of schizophrenia.

Clinical Effectiveness of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Adult Obsessive-Compulsive Disorder (OCD) Treatment: A Systematic Review.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that affects approximately 2% of the human population. Traditional treatment of OCD includes selective serotonin reuptake inhibitor (SSRI) or serotonin reuptake inhibitor (SRI) treatment along with cognitive behavioral therapy (CBT). Nearly 25%-30% of OCD patients do not respond to SSRIs. Glutamatergic agents are currently being studied for the treatment of OCD due to the glutamatergic pathway in the brain, related to OCD, and the role of the cortico-striato-thalamic circuit (CSTC). This review assesses the clinical effectiveness of N-methyl-D-aspartate (NMDA) antagonists, ketamine/esketamine, memantine, and amantadine, for adult patients with OCD. Inclusion criteria include human studies published within the last 15 years, with patients diagnosed with OCD, aged over 18 years, with only psychiatric comorbidities, and full-text articles. Papers that included interventions other than CBT, exposure with response prevention (ERP), and SSRI/SRI were excluded. Articles were searched for using PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online, GeorgiA LIbrary LEarning Online, EBSCO Information Services, OpenAthens, Multidisciplinary Digital Publishing Institute, and Google Scholar databases, last searched on December 2, 2022. The risk of bias was assessed using Cochrane Risk of Bias tools, the Scale for the Assessment of Narrative Review Articles (SANRA) checklist for literature reviews, and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for quasi-experimental studies. Results were presented and synthesized by Excel spreadsheet analysis. The database search yielded 4,221 articles, which was cut down to 18 articles by inclusion/exclusion criteria, including duplications. 80% of the ketamine studies resulted in a significant reduction of obsessions and compulsions based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and each of the memantine and amantadine studies displayed clinical effectiveness, also. Limitations include the small number of amantadine studies and the limited availability of other NMDA receptor (NMDAR) antagonist-focused studies. This systematic review shows that ketamine is an effective drug for the treatment of non-refractory, mild to moderate OCD, and memantine and amantadine are effective augmentation agents for the treatment of mild to severe OCD.

Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression.

Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8 SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10 mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.

4-F-PCP, a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism.

Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4 -F-PCP analog is a novel PCP analog that is also an NMDA receptor antagonist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its effects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.

Effects of brotizolam as a co-agent with ketamine for induction of anaesthesia in calves.

Anaesthesia in food producing animals in the EU and UK is legally limited to a narrow choice of drugs; the only licensed benzodiazepine being brotizolam. The aim of this study was to investigate the effects of brotizolam as a co-agent with ketamine on the quality of induction, intubation, muscle relaxation and recovery from isoflurane anaesthesia. Seventeen calves were enrolled in this prospective, blinded, randomized experimental study. Calves were sedated with 0.05 mg/kg xylazine and 0.1 mg/kg butorphanol IV. After assessing the quality of sedation, anaesthesia was induced with 2 mg/kg ketamine (group KETA) or 2 mg/kg ketamine with 2 µg/kg brotizolam IV (group BROTI). An additional 1 mg/kg ketamine was administered IV every 2 min until intubation was possible. Anaesthesia was maintained with isoflurane in a mixture of oxygen and air. The amount of ketamine required, quality of induction, intubation, muscle relaxation, and recovery were scored and compared between groups using ordinal regression models (P < 0.05 was considered statistically significant). Sedation scores did not differ significantly between groups but were positively associated with the quality of recovery (P = 0.0098). Group BROTI was associated with a lower quality of induction (P < 0.0001), intubation (P = 0.0203) and muscle relaxation (P = 0.0043). The sedation score and treatment had no effect on the number of attempts of intubation, additional ketamine doses, time to extubation and recovery time. Brotizolam had a negative effect on the quality of induction, intubation, and muscle relaxation compared to ketamine alone. We do not recommend using brotizolam under these circumstances.

Modulation of cholinergic, GABA-ergic and glutamatergic components of superior colliculus affect REM sleep in rats.

The superior colliculus (SC) is associated with visual attention, spatial navigation, decision making, escape and approach responses, some of which are important for defence and survival in rodents. SC helps in initiating and controlling saccadic eye movements and gaze during wakefulness. It is also activated during rapid eye movement (REM) sleep associated rapid eye movements (REMs). To investigate the contribution of SC in sleep-wake behaviour, we have demonstrated that manipulation of SC with scopolamine, carbachol, muscimol, picrotoxin and MK-801 decreased the amount of REM sleep. We observed that scopolamine and picrotoxin as well as muscimol decreased REM sleep frequency. MK-801 decreased percent amount of REM sleep, however, neither the frequency nor the duration/episode was affected. The cholinergic and GABA-ergic modulation of SC affecting REM sleep may be involved in REM sleep associated visuo-spatial learning and memory consolidation, which however, need to be confirmed. Furthermore, the results suggest involvement of efferent from SC in modulation of sleep-waking via the brainstem sleep regulating areas.

Structural Scaffolds as Anti- Alzheimer Agents.

BACKGROUND: Understanding the cognitive and behavioral aspects of Alzheimer's disease- related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity. METHODS: This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi-target anti-Alzheimer drug discovery programs. RESULTS: Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and a few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease. CONCLUSION: This includes the study of workable pharmacophoric groups/combinations, receptors/ enzymatic systems and related hypotheses to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding of this Disease.

Effects of ketamine on rat social behavior as analyzed by DeepLabCut and SimBA deep learning algorithms.

Traditional methods of rat social behavior assessment are extremely time-consuming and susceptible to the subjective biases. In contrast, novel digital techniques allow for rapid and objective measurements. This study sought to assess the feasibility of implementing a digital workflow to compare the effects of (R,S)-ketamine and a veterinary ketamine preparation Vetoquinol (both at 20 mg/kg) on the social behaviors of rat pairs. Historical and novel videos were used to train the DeepLabCut neural network. The numerical data generated by DeepLabCut from 14 video samples, representing various body parts in time and space were subjected to the Simple Behavioral Analysis (SimBA) toolkit, to build classifiers for 12 distinct social and non-social behaviors. To validate the workflow, previously annotated by the trained observer historical videos were analyzed with SimBA classifiers, and regression analysis of the total time of social interactions yielded R 2 = 0.75, slope 1.04; p < 0.001 (N = 101). Remarkable similarities between human and computer annotations allowed for using the digital workflow to analyze 24 novel videos of rats treated with vehicle and ketamine preparations. Digital workflow revealed similarities in the reduction of social behavior by both compounds, and no substantial differences between them. However, the digital workflow also demonstrated ketamine-induced increases in self-grooming, increased transitions from social contacts to self-grooming, and no effects on adjacent lying time. This study confirms and extends the utility of deep learning in analyzing rat social behavior and highlights its efficiency and objectivity. It provides a faster and objective alternative to human workflow.

Conventional Versus New Treatment: Comparing the Effects of Acetylcholinesterase Inhibitors and N-Methyl-D-Aspartate Receptor Antagonist With Aducanumab.

Alzheimer's dementia (AD) is the most common major neurocognitive impairment and the fifth leading cause of death in older adults in the United States. The diagnosis is clinical; however, laboratory tests and imaging frequently rule out secondary causes of dementia. Unfortunately, the treatment available for AD does not reverse dementia, but it may help improve the symptoms and slow the progression of the disease. The conventional treatment - acetylcholinesterase inhibitor (AChEI) therapy and N-methyl-D-aspartate (NMDA) receptor antagonist - is considered to enhance executive function, overall cognition, and activities of daily living. AChEIs such as donepezil, rivastigmine, and galantamine are approved for mild-to-moderate dementia. Furthermore, memantine, an NMDA receptor antagonist, is authorized for moderate-to-severe dementia. Aducanumab, the newest drug available, is an amyloid-beta (Aß) monoclonal antibody approved only for mild AD. Treatment with either AChEIs or memantine is more cost-effective than aducanumab and the best supportive care. Aducanumab has particular recommendations with strict monitoring and several adverse effects, including amyloid-related imaging abnormalities. The most common adverse effects of AChEIs and memantine include gastrointestinal symptoms, dizziness, confusion, and headaches. Therefore, monitoring should be performed periodically at the clinician's discretion for clinical response and tolerability of medication. Conventional therapies are only for symptom management but are still beneficial to patients and caregivers. Unfortunately, at this time, aducanumab's risks outweigh the benefits with a questionable approval process by the Food and Drug Administration (FDA). However, given the potential disease-modifying capabilities of aducanumab, other disease-modifying options may become available by possibly reducing inflammation, preventing Aß plaques from clumping, or keeping tau proteins from tangling.

Targeting NMDA Receptor Complex in Management of Epilepsy.

N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology of seizure disorders and epilepsy. Accordingly, NMDAR modulators have been shown to exert anticonvulsive effects in various preclinical models of seizures, as well as in patients with epilepsy. In this review, we provide an update on the pathologic role of NMDARs in epilepsy and an overview of the NMDAR antagonists that have been evaluated as anticonvulsive agents in clinical studies, as well as in preclinical seizure models.

Use of Riluzole for the Treatment of Hereditary Ataxias: A Systematic Review.

Ataxia is a constellation of symptoms that involves a lack of coordination, imbalance, and difficulty walking. Hereditary ataxia occurs when a person is born with defective genes, and this degenerative disorder may progress for several years. There is no effective cure for ataxia, so we need to search for new treatments. Recently, interest in riluzole in the treatment of ataxia has emerged. We conducted this systematic review to analyze the safety and efficacy of riluzole for treating hereditary ataxia in recent clinical trials. We conducted a systematic review using PubMed and Google Scholar as databases in search of this relationship. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocols to conduct this study. For inclusion criteria, we included full-text clinical trials on humans written in English and found three clinical trials. We excluded case reports, literature reviews, systematic reviews, and meta-analyses for this analysis. We aimed to evaluate the Scale for the Assessment and Rating of Ataxia (SARA) score, the International Cooperative Ataxia Rating Scale (ICARS) score, and the safety of the medication. Two out of the three clinical trials showed statistically significant clinical improvement in the ICARS and SARA scores, while the other trial did not show improvement in the clinical or radiological outcomes. The drug was safe in all clinical trials. Overall, the results of this analysis of riluzole for the treatment of hereditary ataxia are encouraging. Further clinical trials are needed to investigate the efficacy of riluzole on hereditary ataxia.

Pharmacogenetics of Donepezil and Memantine in Healthy Subjects.

Donepezil and memantine are the most common drugs used for Alzheimer's disease. Their low effectiveness could partly be explained by genetic factors. Thus, we aim to identify Single Nucleotide Polymorphisms (SNPs) associated with pharmacokinetics, pharmacodynamics, and the safety of donepezil and memantine. For this regard, 25 volunteers enrolled in a bioequivalence clinical trial were genotyped for 67 SNPs in 21 genes with a ThermoFisher QuantStudio 12K Flex OpenArray. The statistical strategy included a univariate analysis that analyzed the association of these SNPs with pharmacokinetic parameters or the development of adverse drug reactions (ADRs) followed by a Bonferroni-corrected multivariate regression. Statistical analyses were performed with SPSS software v.21 and R commander (version v3.6.3). In the univariate analysis, fourteen and sixteen SNPs showed a significant association with memantine's and donepezil's pharmacokinetic parameters, respectively. Rs20417 (PTGS2) was associated with the development of at least one ADR. However, none of these associations reached the significance threshold in the Bonferroni-corrected multivariate analysis. In conclusion, we did not observe any significant association of the SNPs analyzed with memantine and donepezil pharmacokinetics or ADRs. Current evidence on memantine and donepezil pharmacogenetics does not justify their inclusion in pharmacogenetic guidelines.

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells.

Type 2 diabetes mellitus (T2DM) remains one of the most pressing health issues facing modern society. Several antidiabetic drugs are currently in clinical use to treat hyperglycaemia, but there is a need for new treatments that effectively restore pancreatic islet function in patients. Recent studies reported that both murine and human pancreatic islets exhibit enhanced insulin release and ß-cell viability in response to N-methyl-D-aspartate (NMDA) receptor antagonists. Furthermore, oral administration of dextromethorphan, an over-the-counter NMDA receptor antagonist, to diabetic patients in a small clinical trial showed improved glucose tolerance and increased insulin release. However, the effects of NMDA receptor antagonists on the secretion of the incretin hormone GLP-1 was not tested, and nothing is known regarding how NMDA receptor antagonists may alter the secretion of gut hormones. This study demonstrates for the first time that, similar to ß-cells, the NMDA receptor antagonist MK-801 increases the release of GLP-1 from a murine L-cell enteroendocrine model cell line, GLUTag cells. Furthermore, we report the 3' mRNA expression profiling of GLUTag cells, with a specific focus on glutamate-activated receptors. We conclude that if NMDA receptor antagonists are to be pursued as an alternative, orally administered treatment for T2DM, it is essential that the effects of these drugs on the release of gut hormones, and specifically the incretin hormones, are fully investigated.