Current Neuropharmacology - Online First

Previous studies in drug-naïve, first-episode patients with schizophrenia (FES) suggest glucose metabolism differences in the early stage of psychosis. However, we have limited knowledge of abnormalities in glucose metabolism in young and drug-naïve FES patients.

A total of 162 drug-naïve patients with schizophrenia (aged from 18 to 35 years) and 110 age-, sex-matched healthy control subjects were enrolled. Fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) index were measured in patients and control subjects.

We found that young drug-naïve FES patients exhibited abnormal glucose metabolism compared with control subjects. Fasting insulin, fasting glucose, and HOMA-IR were higher in patients than in controls (all p<0.05). In addition, female patients had significantly higher fasting insulin levels and HOMA-IR than male patients (both p<0.05), as well as in the healthy controls. Binary logistic regression analysis further identified that smoking status, HOMA-IR, and HbA1c were the contributing factors to schizophrenia, after controlling for age and sex.

This study suggests abnormal glucose metabolism in young drug-naïve FES patients, highlighting that these glucose metabolic issues are present at the very early stage of the disease. The identification of abnormal glucose metabolism at the early stages of schizophrenia provides insights into the biological underpinnings of schizophrenia and may lead to more targeted interventions for patients in the early stages of the disease.

Accurate and non-invasive grading of glioma brain tumors from MRI scans is challenging due to limited labeled data and the complexity of clinical evaluation. This study aims to develop a robust and efficient deep learning framework for improved glioma classification using MRI images.

A multi-stage framework is proposed, starting with SimCLR-based self-supervised learning for representation learning without labels, followed by Deep Embedded Clustering to extract and group features effectively. EfficientNet-B7 is used for initial classification due to its parameter efficiency. A weighted ensemble of EfficientNet-B7, ResNet-50, and DenseNet-121 is employed for the final classification. Hyperparameters are fine-tuned using a Differential Evolution-optimized Genetic Algorithm to enhance accuracy and training efficiency.

EfficientNet-B7 achieved approximately 88-90% classification accuracy. The weighted

ensemble improved this to approximately 93%. Genetic optimization further enhanced accuracy by 3-5% and reduced training time by 15%.

The framework overcomes data scarcity and limited feature extraction issues in traditional CNNs. The combination of self-supervised learning, clustering, ensemble modeling, and evolutionary optimization provides improved performance and robustness, though it requires significant computational resources and further clinical validation.

The proposed framework offers an accurate and scalable solution for glioma classification from MRI images. It supports faster, more reliable clinical decision-making and holds promise for real-world diagnostic applications.

Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses.

We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included “MAPT haplotype,” “Alzheimer's disease,” “H1 H2,” “tau pathology,” and “pharmacogenetics.” We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results.

The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles.

The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for population-tailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology.

MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.

Frontotemporal dementia (FTD) is the third most frequent dementia and the leading dementia subtype in individuals under 65. The discovery of C9orf72 (chromosome 9 open reading frame 72) GGGGCC abnormal expansion is a major genetic cause of both FTD and amyotrophic lateral sclerosis (ALS), linking these diseases along a clinicopathological spectrum. This study aimed to depict the research landscape of C9orf72 in FTD over the past decade, track emerging research hotspots, and provide insights into under-researched areas.

Based on the Web of Science database, a bibliometric analysis was conducted to explore publication trends, key contributors, funding sources, journal categories, co-authorship networks, and keyword co-occurrence, clustering, and bursts.

A total of 1,220 articles were identified, with sustained output of over 100 articles annually. The majority of contributions and funding support came from North America and Europe. Hot research themes included hexanucleotide repeats, nucleocytoplasmic transport, disease mechanisms, and therapeutic targets.

North America and Europe were highly productive, supported by higher regional prevalence, genetic burden, and robust funding. Ploy-GR in cerebrospinal fluid has emerged as a diagnostic biomarker. Pathogenic mechanisms remain complex, involving both gain- and loss-of-function effects. Metformin and antisense oligonucleotides were considered as potential therapeutics. Further research is needed in underrepresented populations and on the translational potential of emerging molecular targets.

This study offers a comprehensive overview of current trends and future directions over the past decade in C9orf72-related FTD research, allowing researchers—particularly those new to the area—to quickly understand the current landscape.

Amyloid-beta-targeting monoclonal antibodies (mAbs) for Alzheimer's disease frequently induce amyloid-related imaging abnormalities with hemorrhage (ARIA-H), yet systematic comparisons of ARIA-H incidence across therapeutic agents remain limited. Post-approval research prioritizes dosing over mechanism, leaving unresolved whether ARIA-H variations originate from intrinsic mAb properties. We address two gaps: comparative ARIA-H risk stratification among clinically available/investigational mAbs, and elucidation of structural/functional features influencing ARIA-H susceptibility.

A systematic comparison of seven mAbs (donanemab, aducanumab, bapineuzumab, lecanemab, gantenerumab, crenezumab, solanezumab) was conducted, analyzing clinical trial data and molecular characteristics.

ARIA-H incidence ranked as follows (highest to lowest): donanemab > aducanumab > bapineuzumab > lecanemab > gantenerumab > crenezumab > solanezumab. Five mAb-specific determinants emerged: (1) Types of Aβ Binding: Enhanced clearance of mature amyloid plaques correlated with elevated ARIA-H risk. (2) Polymer binding Affinity: Reduced small oligomer-binding capacity predicted higher ARIA-H incidence. (3) Epitope location: N-terminal-targeting mAbs showed greater ARIA-H incidence vs. mid/C-terminal binders. (4) Fc region structure: IgG4-based constructs showed higher ARIA-H incidence than IgG1 analogs. (5) Clearance kinetics: Rapid attainment of amyloid reduction thresholds amplified ARIA-H incidence.

We identify a risk hierarchy for ARIA-H among anti-Aβ mAbs and link specific mAb biophysical properties—Aβ binding type, affinity for soluble oligomers, epitope specificity, Fc structure, and plaque clearance dynamics—directly to ARIA-H pathogenesis.

These findings establish a mechanistic framework for ARIA-H risk and provide concrete molecular predictors to guide antibody engineering strategies. Prioritizing mAbs with controlled amyloid clearance, C-terminal binding domains, and IgG1 frameworks may enhance therapeutic safety, advancing precision immunotherapy for Alzheimer's disease.

Facial nerve injury induces autophagy and apoptosis in facial nerve nucleus motoneurons of the CNS, impairing nerve regeneration and functional recovery. The function of P2Y2R after facial nerve injury remains to be determined. This study hypothesizes that inhibiting P2Y2R may play a protective role in facial nerve injury by modulating the autophagy signaling pathway.

An in vivo mouse model of facial nerve crush injury was utilized in this study. Mice received either a P2Y2R agonist or antagonist through intrathecal injections of 10 μL/daily for 4 weeks. This study measured facial nerve function, examined fibrogenesis, and analyzed expression of autophagy regulatory proteins. In an in vitro experiment, NSC34 cells were treated with a P2Y2R agonist or an antagonist, and changes in the levels of phosphorylated PI3K, Akt, and mTOR, as well as autophagy regulatory proteins determined.

Inhibition of P2Y2R significantly increased autophagy levels and enhanced facial nerve function. These protective outcomes were linked to the suppression of phosphorylated PI3K, Akt, and mTOR signaling pathways.

The study suggests that P2Y2R inhibition may improve facial nerve function by improving autophagy, making it a promising therapeutic approach for treating facial nerve injury.

Numerous studies have demonstrated that efgartigimod is effective in treating myasthenia gravis (MG) across various patient populations. However, there is limited evidence regarding its use in patients with new-onset acetylcholine receptor antibody-positive generalized MG (AChR-gMG). Therefore, this study aimed to investigate the real-world safety and effectiveness of efgartigimod in Chinese patients with new-onset anti-cholinergic receptor (AChR)- gMG.

This prospective study was conducted in 29 patients with new-onset AChR-gMG, with a three-month follow-up. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis score, prednisone dose, laboratory data, and adverse events were assessed at every follow-up visit.

At 4, 8, and 12 weeks, the mean change in MG-ADL scores was 8.13  ±  3.66, 7.41  ±  4.22, and 6.37  ±  4.67, respectively. Compared with the baseline, 96% (28/29) of patients achieved an MG-ADL response (defined as a decrease of ≥2 points), with a mean response time of 0.81 ± 0.53 weeks (5.67 ± 3.71 days). After one cycle, 52% (15/29) of patients achieved minimal symptom expression (MSE), while 41% maintained MSE at 12 weeks. Moreover, 89% and 72% of MG-ADL responders sustained for 8 and 12 consecutive weeks, respectively. Additionally, patients with thymomatous MG exhibited a poorer response to efgartigimod and required two infusion cycles. All patients were able to reduce their daily steroid dose, and the mean daily prednisone dose decreased by 10.73 mg per day. The treatment was well tolerated, and a few mild adverse events were reported.

These results demonstrate the clinical significance of efgartigimod in patients with new-onset AChR-gMG, achieving rapid symptom relief and steroid reduction. Additionally, the potential of efgartigimod to serve as a bridge treatment, facilitating a steady transition to long-term conventional immunosuppressive therapy, was demonstrated. Due to limitations in this study, such as a small sample size, larger randomized controlled trials are needed to validate.

Our study showed that efgartigimod is clinically beneficial and offers rapid symptom control in patients with new-onset AChR-gMG. A more aggressive application of efgartigimod in combination with corticosteroids may lead to a smoother therapeutic transition, which will further maintain favorable conditions.

Dysfunction of the pathway between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) may be responsible for the weaker or lack of efficacy of antidepressant drugs in patients suffering from treatment-resistant depression. This study aims to evaluate the behavioural effects of vHPC lesion with ibotenic acid (IBO) in animals subjected to the chronic mild stress (CMS) procedure and treated with either chronic venlafaxine or acute deep brain stimulation (DBS) in the mPFC. In addition, electrophysiological studies are expected to reveal neuromodulatory effects on the function and plasticity of mPFC neurons in response to stress, lesion, and deep brain stimulation (DBS).

Wistar Han rats were exposed to the chronic mild stress model of depression and IBO lesion in vHPC. The effects of both procedures were evaluated in a series of behavioural tests (sucrose test, elevated plus maze, novel object recognition, and social interaction) and in electrophysiological recordings (field potential recording and LTP induction).

The CMS procedure caused a decrease in sucrose consumption, deficits in cognitive function and social interaction, and increased anxiety. The lesion in vHPC with IBO resulted in similar behavioral changes. Repeated (5 weeks) administration of venlafaxine (10 mg/kg, IP) reversed these deficits in stressed animals but was only partially effective in reversing the effects of IBO lesion in HPC. In contrast, the neuromodulation strategy with DBS of the mPFC produced a robust reversal of all behavioural changes observed in both stressed and lesioned rats. The CMS did not affect the amplitude of field potentials in mPFC slices, but the induction of Long-Term Potentiation was impaired in these animals. The IBO lesion significantly reduced the amplitude of Field potentials as compared to unstressed rats. Both repeated venlafaxine and acute DBS normalized these effects of the IBO lesion.

Observed effects were fully normalized by DBS in mPFC but not by venlafaxine, which only partially reversed the IBO lesion-induced effects. The weaker sensitivity of vHPC-lesioned animals to the therapeutic action of venlafaxine provides further evidence that insufficient transmission from the vHPC to the mPFC could be responsible for antidepressant non-response.

These data support the hypothesis that resistance to antidepressant treatment may result from the inability of antidepressants to fully activate the impaired vHPC-PFC pathway, which could be overcome by the neuromodulatory properties of deep brain stimulation.

The COVID-19 pandemic triggered unprecedented changes in the scholarly publishing landscape, particularly in biomedical fields such as Neurosciences and Neuropharmacology. Several journals experienced steep, short-term increases in citation metrics during 2020-2022. However, it remains uncertain whether these surges reflected a sustainable impact or temporary inflation. This study aimed to analyze post-pandemic bibliometric behavior by evaluating the Rate of Change (RoC) in key journal-level indicators from 2013 to 2023.

A retrospective longitudinal study was conducted on 233 neuroscience journals indexed in the Journal Citation Reports. Six indicators were analyzed: Journal Impact Factor (JIF), Eigenfactor Score, Immediacy Index, Article Influence Score, Cited Half-Life, and Total Citations. RoC was calculated for each metric on an annual basis. Mixed-effects models with random intercepts and slopes were constructed to evaluate longitudinal trajectories and identify changes associated with three defined periods: pre-pandemic (2013-2019), pandemic (2020-2022), and post-pandemic (2023). Subgroup analyses assessed journal quartiles and categories to explore variations in impact resilience.

The pandemic period (2020-2022) showed significant increases in RoC for JIF (mean β = +4.85, p = 0.004), Immediacy Index (β = +6.22, p = 0.002), and Total Citations (β = +5.88, p < 0.001). These changes were more prominent in top-quartile journals and those classified under Neuropharmacology. In contrast, alternative metrics such as the Eigenfactor Score and Article Influence Score remained relatively stable across the same period. In 2023, most indicators exhibited a normalization trend, with JIF and Immediacy Index showing marked deceleration in RoC, suggesting a post-pandemic recalibration. Journals with sustained positive trajectories were primarily concentrated in high-impact clusters, with Current Neuropharmacology ranking among the top performers by RoC slope.

The findings demonstrate that the surge in citations during the pandemic was primarily transitory and varied across bibliometric indicators. Traditional metrics like JIF and Immediacy Index were more sensitive to systemic shocks, while influence-based indicators (Eigenfactor and Article Influence Score) showed higher temporal resilience. The application of RoC allowed for a nuanced interpretation of metric trajectories and minimized misinterpretation of short-term spikes. Limitations include reliance on publicly available data and potential lag effects in citation behavior not fully captured within the 10-year window.

This study reveals that pandemic-era citation inflation in Neuroscience journals was largely temporary and metric-dependent. RoC-based modeling offers a reproducible and adaptable approach for assessing the sustainability of bibliometric trends. These insights can help editors, funders, and academic institutions better understand journal performance, make informed decisions about research dissemination, and refine metrics-based evaluation frameworks in the post-pandemic publishing environment.

Cerebral ischemia (CI) is a severe neurological disorder characterized by high incidence and disability rates. Its pathogenesis is complex, involving multiple interrelated biological processes. Among these, intercellular communication has emerged as a key mechanism regulating the damage and recovery phases of CI. It controls information exchange between cells, thereby playing a crucial role in cellular responses to ischemic injury. Understanding how intercellular communication promotes the pathophysiology of CI may provide valuable insights into new therapeutic targets.

To elucidate the role of intercellular communication in CI, recent literature was analyzed, with a focus on how intercellular communication influences cellular behaviors and metabolism. This review integrates data from molecular biology, cellular signaling studies, and cerebral ischemia models.

Studies indicate that intercellular communication significantly influences the progression and outcomes of CI. Intercellular communication not only participates in regulating the inflammatory response following injury but also plays a dual role in neuroprotection and regeneration.

The dual role of intercellular communication—exacerbating damage through inflammatory cascades and promoting recovery through neuroprotective mechanisms—highlights its complex contribution to the pathology of CI. Cellular crosstalk between neurons, glial cells, endothelial cells, and immune cells coordinates the dynamic response to ischemic injury. Understanding these dynamics offers promising opportunities for targeted interventions.

Intercellular communication plays a central role in the mechanisms of injury and repair in cerebral ischemia. By influencing inflammation, neuroprotection, and regeneration, it serves as both a mediator of injury and a potential therapeutic target. Further research is needed to fully elucidate these mechanisms and translate them into effective clinical strategies for treating CI.

This study investigates the relationship between National Cancer Institute Common Terminology Criteria (NCI-CTC) for grading bortezomib-induced peripheral neuropathy (BIPN) and objective motor/sensory nerve dysfunctions assessed by nerve conduction studies (NCS). It also evaluates the correlation between specific nerve conduction abnormalities and progression-free survival (PFS).

Thirty-three patients with multiple myeloma developing peripheral neuropathy during bortezomib treatment were enrolled. Participants were grouped based on NCI-CTC toxicity scores (< 2, n=17; ≥ 2, n=16). Comprehensive NCS were performed, assessing compound muscle action potentials (CMAP), motor conduction velocities (MCV), sensory nerve action potentials (SNAP), and sensory conduction velocities (SCV) across ulnar, median, tibial, peroneal, sural, and superficial peroneal nerves. Correlation analyses were used to examine the association between NCS parameters and PFS.

Patients with higher NCI-CTC grades (≥ 2) exhibited significant reductions in motor and sensory nerve conduction parameters. Notably, the peroneal nerve showed significant decreases in CMAP (p=0.0059) and MCV (p=0.0223). The superficial peroneal nerve displayed a significant reduction in SCV (p=0.0189). A strong positive correlation was found between median nerve SNAP and longer PFS (r=0.558, p=0.001).

The findings indicate that higher clinical grades of BIPN (NCI-CTC ≥ 2) are associated with objective neurophysiological evidence of worsened nerve function, with the peroneal nerve being particularly affected. The correlation between median nerve SNAP and PFS suggests that NCS parameters could potentially serve as prognostic markers in patients with BIPN.

Bortezomib-induced neurotoxicity leads to significant impairments in both motor and sensory nerve conduction. Median nerve SNAP shows promise as a predictor for PFS, underscoring the potential value of NCS in monitoring neurotoxicity and guiding clinical management in patients receiving bortezomib.

Multiple Sclerosis (MS) is characterized by the infiltration of leukocytes into the nervous tissue, and disruption of the Blood-Brain Barrier (BBB) is one of the main factors in the progression of MS and its model, Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, some anti-lymphocytic drugs against MS may inherently produce BBB disruption as their side effect. This study hypothesized that drugs restoring the BBB may be useful for the treatment of MS and EAE, as well as for ameliorating the side effects of modern anti-lymphocytic drugs.

EAE was induced in SJL/J mice. EAE progression was evaluated by a severity score and a plasma cytokine profile, while a BBB condition was evaluated by the Evans dye method, Tight Junction Proteins (TJPs) content, and leukocyte infiltration.

The mice with EAE demonstrated neurological symptoms, a cytokine response, and BBB deterioration, which was associated with upregulation of the NADPH oxidases NOX1 and NOX4 in the brain. Administration of the anti-lymphocyte drug fingolimod to EAE mice caused lymphopenia, improved animal health, enhanced the BBB function during the administration period, and decreased the pro-inflammatory response, but it was accompanied by a “withdrawal effect,” defined as a sharp increase in the IL-17 and IFN-gamma to levels higher than those in untreated animals, lymphocyte hyperactivation, worsening symptoms, and increasing BBB permeability after discontinuation of fingolimod. Administration of peroxiredoxin 6 (Prdx6) to EAE mice also improved BBB, decreased lymphocyte infiltration and NADPH oxidase expression, and ameliorated symptoms. Preliminary administration of Prdx6 before the fingolimod treatment eliminated the “withdrawal effect” of fingolimod and led to full recovery of the EAE mice. This Prdx6 effect was associated with the activation of anti-proliferative and pro-apoptotic signaling cascades in lymphocytes.

Conclusion: Both fingolimod and Prdx6 produced beneficial effects, while Prdx6 may be useful for ameliorating the side effects of anti-lymphocytic drugs. Accounting for literature data that discontinuation of MS treatment is very likely to lead to a severe MS rebound, a drug that prevents the rebound should be useful.

Maternal chronic immune and inflammatory conditions may predispose newborns to atypical developmental trajectories, identifying pregnancy as a key period for the etiopathogenesis of neurodevelopmental disorders. The possible long-term impact of maternal multiple sclerosis (MS) on the offspring’s cognitive and behavioral development and its pharmacological treatment during pregnancy is mostly unknown. This study aims to delineate the cognitive and behavioral profile of offsprings exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, in comparison to a control group.

We retrospectively enrolled 39 children (23 males; 16 females; mean age 45.82 ± 35.46 months) exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, and 36 children (24 males; 12 females, mean age 38.03 ± 21.52 months) of healthy mothers. All offspring underwent a standardized evaluation of their intellectual or developmental quotient, adaptive functioning, and behavioral issues, including symptoms of autism.

The clinical profile of the included offspring was characterized by an adequate cognitive profile and a good level of adaptive skills (MS offspring: Griffiths III mean total DQ (N = 30) 114.57; WISC-IV mean Full IQs (N= 9) 115.44; mean ABAS GAC 97.28/Control offspring: Griffiths III mean total DQ (N = 31) 105.42; WISC-IV mean Full IQs (N= 4) 119.25 ± 11.32; mean ABAS GAC 97.82 ± 21.4). Furthermore, no significant behavioural problems or autism symptoms emerged in the entire group, regardless of MS treatment.

Offspring's developmental and behavioral phenotypes do not appear to be influenced by maternal treatment with Natalizumab until late pregnancy, nor by maternal variables directly related to MS (age at the time of MS diagnosis, disease duration, and severity).