Search Results (189)

Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Alzheimer’s disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis, having only symptomatic effects. Thus, the priority remains prevention and clarifying AD etiology. A better understanding of the neuroprotective mechanisms undertaken by specific genes is crucial to guide the design of novel therapeutic agents via selective ligands and precision medicine. In this review, we present a perspective of the physiological phase of the AD spectrum, of risk factors in AD with a focus on therapeutic approaches in three categories: neurotransmitters/ion modulations, peptide deposit control and aspecific treatments, followed by a discussion of treatment limitations. An overview of innovative strategies and non-pharmaceutical ancillary support is given. Full article

Ketamine infusion therapy has gained recognition as an innovative treatment for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects. Its therapeutic promise is increasingly understood to involve molecular and neurobiological processes that promote neural plasticity and cognitive flexibility. These changes may create a unique window for psychotherapeutic interventions to take deeper effect. This retrospective chart review examined the clinical outcomes of individuals with TRD who received either single or repeated ketamine infusion(s), with or without weekly psychotherapy. Depression severity, measured by Beck Depression Inventory scores, was assessed pre-treatment and 30 days post-infusion(s). The results showed significant symptom reduction across all groups, with the most pronounced effects observed in those who received concurrent psychotherapy. While infusion number did not significantly alter outcomes, the integration of ketamine with psychotherapy appeared to enhance treatment response. Full article

Background: To overcome the limitations of conventional CRC (colorectal cancer) mouse models in replicating metastasis and enabling efficient therapeutic evaluation, we developed a novel implantation method using tissue adhesive to establish reproducible orthotopic and metastatic tumors. Conventional models using injection or suturing techniques often suffer from technical complexity, inconsistent tumor establishment, and limited metastatic reliability. Methods: We developed and validated a novel orthotopic and metastatic CRC model utilizing tissue adhesive for tumor transplantation. Uniform tumor fragments derived from bioluminescent HCT116/Luc xenografts were affixed to the cecum of nude mice. Tumor growth and metastasis were monitored through bioluminescence imaging and confirmed by the results of histological analysis of metastatic lesions. The model’s utility for therapeutic testing was evaluated using MK801, an NMDA receptor antagonist. Results: The biological-based model demonstrated rapid and reproducible tumor implantation (<5 min), consistent primary tumor growth, and robust metastasis to the liver and lungs. The biological-based approach achieved 80% tumor engraftment (4/5), with consistent metastasis to the liver and lungs in all mice, compared with lower and variable metastasis rates in injection (0%, 0/5) and suturing (20%, 1/5) methods. MK801 treatment significantly suppressed both primary tumor growth and metastasis, validating the model’s suitability for preclinical drug evaluation. Conclusions: By enabling rapid, reproducible, and spontaneous formation of metastatic lesions using a minimally invasive tissue adhesive technique, our model represents a significant methodological advancement that supports high-throughput therapeutic screening and bridges the gap between experimental modeling and clinical relevance in colorectal cancer research. Full article

Background/Objectives: Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by progressive neurodegeneration, resulting in cognitive impairment and structural brain changes. Although no curative treatment exists, pharmacological therapies like cholinesterase inhibitors and NMDA receptor antagonists may deliver symptomatic relief and modestly delay disease progression. Structural magnetic resonance imaging (sMRI) is a commonly utilized modality for the diagnosis of brain neurological diseases and may indicate abnormalities. However, improving the recognition of discriminative characteristics is the primary difficulty in diagnosis utilizing sMRI. Methods: To tackle this problem, the Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOA-MIDL) system is presented for the prodromal phase of mild cognitive impairment (MCI) and the initial detection of AD. Results: An attention technique to estimate the weight of every case is presented: the fuzzy salp swarm algorithm (FSSA). The swarming actions of salps in oceans serve as the inspiration for the FSSA. When moving, the nutrient gradients influence the movement of leading salps during global search exploration, while the followers fully explore their local environment to adjust the classifiers’ parameters. To balance the relative contributions of every patch and produce a global distinct weighted image for the entire brain framework, the attention multi-instance learning (MIL) pooling procedure is developed. Attention-aware global classifiers are presented to improve the understanding of the integral characteristics and form judgments for AD-related categorization. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker, and Lifestyle Flagship Study on Ageing (AIBL) provided the two datasets (ADNI and AIBL) utilized in this work. Conclusions: Compared to many cutting-edge techniques, the findings demonstrate that the FOA-MIDL system may determine discriminative pathological areas and offer improved classification efficacy in terms of sensitivity (SEN), specificity (SPE), and accuracy. Full article

Current therapies for Alzheimer’s disease (AD) includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aβ)/Tau-targeting drugs. While these drugs improve cognitive decline and target the pathological mechanisms, their outcomes still are still in debate. Mesenchymal stem cells (MSCs) offer a regenerative approach by modulating neuroinflammation and promoting neuroprotection. Although the paracrine of MSCs is efficient in various AD preclinical studies and the exosomes of MSCs have entered clinical trials, the key cytokines driving the efficacy remain unclear. Here, we evaluated human umbilical cord-derived MSCs (hUC-MSCs) and employed gene-silenced MSCs (siHGF-MSCs, siTNFR1-MSCs, siBDNF-MSCs) in APP/PS1 AD mice to investigate specific mechanisms. hUC-MSCs significantly reduced Aβ/Tau pathology and neuroinflammation, with cytokine-specific contributions: silencing HGF predominantly reduced Aβ/Tau clearance, although silencing TNFR1 or BDNF showed modest effects; silencing TNFR1 or BDNF more prominently weakened anti-neuroinflammation, while silencing HGF exerted a weaker influence. All three cytokines partially contributed to oxidative stress reduction and cognitive improvements. Our study highlights MSC-driven AD alleviation as a multifactorial strategy and reveals specific cytokines alleviating different aspects of AD pathology. Full article

Neuropathic pain resulting from injury to the somatosensory nervous system affects approximately 6.9–10% of the general population and significantly impacts quality of life. Common presentations include burning, stabbing, tingling, or electrical sensations, occurring spontaneously or through hyperalgesia or allodynia. Treatment approaches follow a tiered system. First-line therapies include gabapentinoids (e.g., gabapentin, pregabalin), which target voltage-gated calcium channels; tricyclic antidepressants (e.g., amitriptyline, nortriptyline); and serotonin-norepinephrine reuptake inhibitors such as duloxetine. Second-line options encompass topical agents (e.g., 5% lidocaine, 8% capsaicin), opioid-like medications (e.g., tramadol, tapentadol), and adjunctive therapies including psychological therapies and lifestyle interventions. For refractory cases, third-line treatments include NMDA receptor antagonists (e.g., ketamine, dextromethorphan), cannabinoids, and botulinum toxin type A, though these have more limited clinical evidence. Procedural interventions such as spinal cord stimulation and transcutaneous electrical nerve stimulation provide alternatives when pharmacological approaches fail. Despite advances in treatment options, many patients remain undertreated, highlighting the need for individualized, multimodal approaches and continued research into the complex pathophysiology of neuropathic pain conditions. Full article

The NOS1AP gene encodes the nitric oxide synthase 1 adaptor protein (NOS1AP), which binds to neuronal nitric oxide synthase (nNOS) and regulates nitric oxide (NO) production by dissociating nNOS from NMDA receptors (NMDARs). Notably, NOS1AP expression is upregulated upon NMDAR activation; however, there is no available data regarding its production under the receptor inhibition. The NOS1AP gene is also 1 among more than 1000 genes that are presumed to be associated with the development of schizophrenia. Various animal models of this disorder have been developed, some of which are based on the use of NMDAR antagonists such as dizocilpine (MK-801). In this study, we investigated the expression and production of NOS1AP in rats injected with a low dose of dizocilpine (0.1 mg/kg), as well as in SH-SY5Y and HEK293T cell lines treated with varying concentrations of the same compound (10–200 µM). According to our results, neither the expression of the NOS1AP gene nor the production of NOS1AP protein was affected by dizocilpine treatment. Full article

All human clinical trials evaluating neuroprotective therapeutics in cerebral ischemia have failed, casting a pall over the field which has not recovered. Numerous methodological issues in the performance of these trials were identified, with the result that current trials are now subject to higher degrees of rigor and transparency. Advances in re-canalization technologies now offer the hope that adjunctive neuroprotection can improve patient outcome. The evaluation of neuroprotection in preclinical animal models has also suffered from methodological issues, which has also been addressed, resulting in an improved performance of studies. This leaves the question of how to actually pick the most appropriate neuroprotective therapy for translation. Given the current limitations in resources, and the numerous strategies that have been proposed to take advantage of clinical and preclinical methodological improvements, we suggest that in vitro studies involving subjecting the most sensitive cells—neurons—to oxygen–glucose deprivation (OGD) can be used to resolve among the many possibilities. Specifically, a large body of evidence shows that successive increases in OGD durations (spanning the lethal/supra-lethal continuum) require increasingly ‘strong’ drugs and combinations to adequately protect neurons (criteria not met in clinical trials). Notably, as the OGD duration is lengthened, NMDA receptor (NMDAR) antagonists of increasing potency and dose are required to match this increasing severity. Under supra-lethal OGD conditions, cocktails composed of anti-excitotoxic antagonists with maximal potency and dose are required to achieve neuroprotection. We propose that this approach can serve as a strategy—a neuroprotective framework—to prioritize among the many possibilities that exist for neuroprotective therapeutics for translation. Specifically, utilize the OGD continuum to compare within-, between- and outside-classes of drugs, first alone and then in combinations, to identify the most efficacious drugs (‘head-to-head’ competitions to identify the ‘last man standing’). While the current state of knowledge strongly suggests that anti-excitotoxic approaches are required, this framework allows the integration of testing established and new therapeutics alike. This framework should include new technologies such as multi-electrode arrays (MEAs), which allow the evaluation of adverse effects of drugs alone, as well as if a drug truly provides functional neuroprotection, and not just survival. The neuroprotective framework provides a comprehensive strategy to eliminate ineffectual treatments, leaving only those modalities with the highest therapeutic index to be prioritized for translation. Full article

Status epilepticus (SE) is a neurological emergency. Current evidence dictates a step-by-step approach with a first line of therapy consisting of benzodiazepines (BDZs). In many situations, the currently approved approach does not terminate a BDZ-resistant SE. This happens in Stage 1 Plus, a framework designed by the author to recognize cases of probable benzodiazepine-resistant status epilepticus even before treatment initiation. These cases include Prolonged SE (SE lasting > 10 min), the absence of prominent motor phenomena, and acute etiology (primary central nervous system etiologies most of all). BDZ-refractory SE cases (Stage 1 Plus) might require a different approach, one targeting the unresponsive GABA signaling state mediated by NMDA/AMPA receptors, such as combined polytherapy with Ketamine from the start. These considerations stem from the receptor trafficking hypotheses: in prolonged seizure activity and primary central nervous system etiologies, GABA receptors get internalized and move away from synapses, and therefore, SE becomes resistant to BDZ. A rational polytherapy that might restore the unresponsiveness to BDZ in SE should include NMDA antagonists, such as Ketamine. Ketamine has proven effective in many experimental models of status epilepticus, and much evidence is gathering supporting its use in humans, especially in refractory and super-refractory SE. We lack studies evaluating combined polytherapy in SE, especially in the early phases. The author suggests here that Ketamine should be used along with first-line BDZ in the early SE stage falling in the category of Stage 1 Plus and as a first-line anesthetic infusion drug in refractory SE, especially in cases progressing from Stage 1 Plus, eventually adding continuous midazolam/propofol infusion in later phases. This systematic review’s objective is to summarize the presently available evidence of the early use of combined polytherapy that includes Ketamine, along with the currently available evidence of Ketamine use in early, established, and refractory SE. Nine studies were included. Boluses of Ketamine and Midazolam are effective in pediatric convulsive Stage 1 Plus SE. The results show that earlier Ketamine administration (especially within 12 h of SE onset) was significantly associated with improved seizure control, with a more favorable safety profile than Midazolam in refractory SE. Notably, a dosage of less than 0.9 mg/kg/h proves ineffective in terminating SE. Ketamine has the advantage of preventing intubation, possibly shortening the length of stay in the intensive care unit. Full article

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

Neuroprotective strategies in coronary artery interventions are essential due to the rising number of high-risk patients undergoing procedures like coronary artery bypass grafting (CABG), totally endoscopic coronary artery bypass (TECAB), and hybrid revascularization. In this review article, we summarize the neurological complications associated with coronary artery disease intervention and the risk mitigation strategies. CABG carries significant risks, including ischemic stroke, encephalopathy, seizures, and peripheral nerve injuries. Risk factors include advanced age, hypertension, diabetes, and atherosclerosis. Off-pump CABG minimizes stroke risk by avoiding aortic manipulation and CPB. TECAB and hybrid revascularization have fewer reported neurological complications but still pose risks of stroke and cranial nerve injuries. Pharmacological neuroprotection includes agents such as barbiturates, volatile anesthetics, lidocaine, NMDA receptor antagonists, magnesium, nimodipine, corticosteroids, and aprotinin. Deep hypothermic circulatory arrest (DHCA) is reserved for complex aortic cases requiring a bloodless surgical field. Intraoperative strategies involve cerebral perfusion monitoring, embolic protection devices, and therapeutic hypothermia. Preoperative optimization targets risk factors, arrhythmia prevention, and antiplatelet therapy management. Postoperatively, timely antiplatelet administration, glucose control, hemodynamic stabilization, and cognitive monitoring are critical. Comprehensive neuroprotective approaches, spanning pre- to postoperative phases, aim to reduce neurological complications and enhance outcomes in coronary interventions. Full article

Background/Objectives: Remifentanil-based anesthesia is linked to opioid-induced hyperalgesia (OIH), increasing postoperative pain and analgesic requirements. Magnesium, an N-methyl-D-aspartate (NMDA) receptor antagonist, might alleviate OIH. We aimed to assess whether intravenous magnesium reduces postoperative pain, analgesic requirements, and hyperalgesia in adults receiving remifentanil-based anesthesia. Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science (1 December 2024) for randomized controlled trials (RCTs) comparing intravenous magnesium vs. placebo. Risk of bias was evaluated with the Cochrane RoB 2 tool, and random-effects meta-analyses were conducted. GRADE was used to assess evidence quality. Primary outcomes were postoperative analgesic requirements and pain scores; secondary outcomes included intraoperative remifentanil consumption, shivering, postoperative nausea/vomiting (PONV), extubation time, hypotension, and bradycardia. PROSPERO registration: CRD42024609911. Results: Twenty-two RCTs (n = 1362) met eligibility. Magnesium significantly decreased 24 h analgesic requirements (standardized mean difference [SMD] −1.51; 95% confidence interval [CI] −2.15 to −0.87; p < 0.0001) and pain scores (SMD −0.61; 95% CI −0.90 to −0.32; p < 0.0001), with benefits persisting up to 48 h. It also reduced intraoperative remifentanil use (SMD −0.52), shivering (odds ratio [OR] 0.25), and PONV (OR 0.66), without prolonging extubation or increasing hypotension/bradycardia risk. High heterogeneity, potential publication bias, and moderate-to-very-low evidence certainty warrant caution. Conclusions: Intravenous magnesium appears beneficial in remifentanil-based anesthesia, but further large-scale, methodologically robust trials are needed to confirm optimal and clarify safety profiles across diverse surgical populations. Full article

Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders. Full article