Current Neuropharmacology - Online First

Treatment-resistant depression (TRD) is a severe psychiatric condition that may increase the risk of suicidal thoughts and self-harming behaviors. Intranasal esketamine has emerged as an effective treatment for TRD, also addressing depression-related emergencies such as suicidal ideation.

This retrospective observational study analyzed 26 outpatients with TRD treated with adjunctive intranasal esketamine alongside ongoing oral antidepressants for 4 weeks. Suicidal ideation and behaviors were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and depressive symptoms were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, week 2, and week 4. Statistical analyses included repeated-measures ANOVA and subgroup analyses by gender and baseline self-harm profile.

Esketamine significantly reduced suicidal ideation and depressive symptoms from baseline to week 2 and week 4 (all p<.001). Additionally, non-suicidal self-harm declined, exhibiting gender-specific patterns: women demonstrated a faster reduction in non-suicidal self-harm, whereas men showed slower improvement in suicidal self-harm. A strong correlation between depressive symptoms and suicidality confirmed their interplay.

In our real-world TRD sample, adjunctive intranasal esketamine led to a rapid and sustained reduction in suicidality and depressive symptoms, with distinct gender-related patterns in self-harm trajectories. These findings may inform individualized monitoring strategies. Limitations include the small sample size, retrospective design, and lack of a control group.

Esketamine rapidly improved suicidality and depression in TRD, with preliminary evidence suggesting gender-specific responses, and highlighting the importance of tailored interventions to maximize outcomes. Further research is needed to confirm these differences, explore the long-term effects, and understand the underlying mechanisms.

The nerve growth factor (NGF) is a crucial neurotrophic factor with the ability to induce neuronal differentiation. However, whether NGF-loaded exosomes (Exo-NGF) can alleviate neuropathic pain in chronic constriction injury (CCI) rats remains unclear.

A neuropathic pain model was established using CCI rats. The pain was assessed using the von Frey test and the hot plate test. Exo-NGF was collected from HEK293 cells transfected with an NGF plasmid. The diameter of Exo-NGF was determined using transmission electron microscopy. Protein levels of inflammatory factors, including IL-18, IL-1β, and TNF-α, were measured using enzyme-linked immunosorbent assay, and their mRNA levels were evaluated using qPCR. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) protein levels were determined using immunostaining and Western blot.

NGF protein and mRNA were highly expressed in Exo-NGF. The mRNA in Exo-NGF was successfully delivered into neural stem cells and promoted their differentiation. Injection of Exo-NGF into the spinal dorsal horn significantly alleviated mechanical allodynia and thermal hyperalgesia. Additionally, Exo-NGF reduced levels of IL-18, IL-1β, and TNF-α. NLRP3 and its key components, including apoptosis-associated speck-like protein and caspase-1, were also reduced by Exo-NGF treatment in CCI rats.

Our findings highlight the therapeutic potential of exosome-based NGF delivery for treating chronic pain conditions.

Exo-NGF significantly alleviates neuropathic pain by suppressing inflammation and NLRP3 activation.

Clozapine, after its introduction, reshaped the landscape of Treatment-Resistant Schizophrenia (TRS) treatment, becoming the first-line treatment for that condition. However, many patients fail to respond to this drug alone. Clozapine-resistant schizophrenia (CRS) is associated with a more severe clinical presentation than TRS, manifesting in exacerbated symptoms and significantly diminished quality of life. The complex nature of CRS has prompted the development of augmentation strategies, which most commonly include another antipsychotic. The present multicenter observational study aimed to assess and compare the efficacy of Lurasidone augmentation alongside clozapine versus other second-generation antipsychotic combinations in patients with a schizophrenia spectrum disorder.

A total of 45 patients with a diagnosis of a schizophrenia spectrum disorder and labeled as “treatment resistant” were included. Functional and psychometric assessments were made at the baseline, one month, and six months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses.

A significant improvement over time was observed in the two groups for both the clinical and functional outcomes assessed, demonstrating the efficacy of a proper augmentation strategy in CRS management. Moreover, significantly lower psychiatric ward admissions were observed in the lurasidone group (p<.05).

Our findings suggest that lurasidone augmentation in CRS offers significant improvements in psychopathological domains similar to alternative augmentation strategies.

Although further studies are needed to confirm our findings, lurasidone’s favorable side-effect profile should be considered.

Increasing evidence indicates a connection between Alzheimer’s disease (AD) and endothelial dysfunction. Given the lack of a definitive cure for AD, the purpose of this research was to explore the impact of a short incubation with plasma samples obtained from 30 patients with sporadic AD and 21 age- and sex-matched control subjects on cultured human aortic endothelial cells (HAECs), as well as to assess the effects of resveratrol (RSV) supplementation to the plasma.

Specifically, the study analyzed: the production of nitric oxide (NO) and peroxynitrite; the activities of superoxide dismutase (SOD) and Na⁺/K⁺-ATPase; membrane fluidity; and levels of thiobarbituric acid-reactive substances (TBARS).

When incubated with AD plasma, cells showed a decrease in NO levels, enzymatic activities, and membrane fluidity, as well as an increase in peroxynitrite and TBARS production, compared to those exposed to plasma from healthy controls. In contrast, supplementation with RSV-enriched plasma, reduced reactive oxygen species (ROS) levels, and enhanced SOD activity. RSV also improved endothelial function, by increasing membrane fluidity, Na^+/K⁺-ATPase activity, and enhancing NO production and bioavailability, potentially benefiting cerebral perfusion.

Though preliminary, our findings highlight the critical role played by vascular health in Alzheimer’s disease, and the potential impact of resveratrol in maintaining the endothelial integrity, thus mitigating the progression of AD .

In conclusion, our study supports the use of dietary natural compounds to reduce oxidative stress and prevent or reverse vascular endothelial dysfunction associated with AD.

Ginsenoside Rg2 (GRg2), a naturally occurring triterpenoid derived from ginseng rhizomes, exhibits neuroprotective properties. Neuroinflammation is recognized as one of the key pathogenic mechanisms underlying Alzheimer's disease (AD). This research aims to investigate the beneficial effects of GRg2 on AD and explore its potential mechanisms.

In APP/PS1 mice, cognitive and behavioral assessments were first performed. Subsequently, brain tissue analyses were performed using immunohistochemical analysis and Western blot. A combined analysis of the gut microbiome and metabolomics was conducted to explore potential mechanisms. Finally, key findings were further validated through immunofluorescence and enzyme-linked immunosorbent assay.

GRg2 enhanced learning, memory, and cognitive functions. And inhibits the deposition of β-amyloid and phosphorylated tau. GRg2 effectively inhibits the production of Bacteroides and Helicobacter. In addition, it reduced the levels of pyruvaldehyde and trimethylamine N-oxide, metabolites closely related to neuroinflammation. GRg2 effectively inhibited the activation of astrocytes and microglia in the brains of APP/PS1 mice, and also reduced the expression of neuroinflammatory mediators IL-6, IL-1β, and TNF-α.

The findings of this study substantiate the neuroprotective efficacy of GRg2, providing a novel therapeutic strategy and theoretical foundation for natural product-based interventions against AD.

GRg2 improves cognitive function and mitigates AD pathology, which is at least partially attributed to its regulation of gut microbiota and metabolites, as well as its anti-neuroinflammatory effects.

Recent evidence increasingly supports a potential role of Perivascular Macrophages (PVMs), a unique subpopulation of brain immune cells, in the pathogenesis of Alzheimer’s disease (AD). Strategically positioned at the brain-vasculature interface, PVMs sense the redox status, modulate immunity, and potentially influence ferroptosis—an iron-dependent form of regulated cell death increasingly implicated in AD. However, whether the involvement of PVMs in AD pathology specifically entails mechanisms related to the crosstalk between immunometabolism and ferroptosis, and the precise molecular pathways linking PVMs, immunometabolism, and ferroptosis to AD, remains unclear.

We first obtained single-cell RNA sequencing data of PVMs from AD patients and control subjects via the GEO database, identified Differentially Expressed Genes (DEGs), and applied Mendelian Randomization (MR), with robustness validated via leave-one-out analysis to pinpoint key genes among the DEGs with causal relevance to AD. Next, we identified ferroptosis-related genes within these key genes and examined their associations with immune cell infiltration and immunometabolic signaling pathways, while also predicting their regulatory transcription factors to inform potential therapeutic strategies.

We identified 149 DEGs in PVMs between AD and control groups, which were primarily enriched in immune and metabolic pathways. MR analysis established eight genes (ACSL1, SPATA6, RAB31, NIBAN1, HDAC4, GRAMD1B, GCC2, and DENND3) as causally and negatively associated with AD risk (IVW analysis identified all P < 0.05, with robustness confirmed by leave-one-out analysis), with ACSL1 being recognized as a known ferroptosis driver. Immune cell infiltration analysis revealed significant differences in monocyte and neutrophil proportions in AD, with DENND3 identified as the sole gene significantly correlated with monocyte abundance. The Key genes demonstrated distinct associations with immunometabolic pathways: GRAMD1B expression was positively associated with PI3K/AKT/mTOR signaling, whereas both NIBAN1 and SPATA6 showed enrichment in cells with high Notch signaling activity. ACSL1 exhibited robust associations with multiple pathways implicated in ferroptosis, including the IL-6/JAK/STAT3, interferon-γ, TGF-β, bile acid metabolism, and cholesterol homeostasis pathways, suggesting potential mechanisms that mediate the crosstalk between immunometabolism and ferroptosis. Transcription factor analysis highlighted shared regulation by CEBPD and the SP1/2/3/4 family, indicating convergent transcriptional control of these genes.

This study identifies eight key genes in PVMs that may protect against AD through mechanisms involving the interplay between immunometabolism and ferroptosis. Our findings provide novel insights into the function of PVMs in AD pathophysiology and suggest potential therapeutic targets for this devastating neurodegenerative disease.

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.