Current Neuropharmacology - Online First

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.

Our team conducted a pharmacogenomics (PGx) analysis to evaluate the interactions between cocaine, glucose metabolism, and functional connectivity using in-depth silico PGx methods.

Utilizing PharmGKB, we extracted PGx annotations related to cocaine, glucose, and dopamine (raw data). After filtering, we refined a list of 49 unrepeated, brain-expressed genes and examined their interactions in a protein-protein interaction (PPI) network through STRING-MODEL, identifying top candidate genes.

Targeting key protein-coding genes with the highest connectivity, we identified COMT, DRD2, and SLC6A3, along with their 17 connected genes. A deep dive into gene-miRNA interactions (GMIs) using NetworkAnalyst revealed that COMT, DRD2, and hsa-miR-16-5p have multiple interactions with OPRM1 and BDNF. Enrichment analysis via Enrichr confirmed that this refined set of 17 impacts dopamine function and are interactive with dopaminergic pathways. Notably, Substance Use disorders (SUD) were the most significant manifestation predicted for the interplays among these genes.

Reviewing all PGx annotations for the 17 genes, we found 4,665 PGx entries, among which 1,970 were significant, with a p-value above 0.045. These were ultimately filtered down to 32 potential PGx annotations excluded in association with “Cocaine,” “Glucose or Diabetes,” and “Dopamine”. Accordingly, 12 Pharmacogenes represented 32 PGx-associated with Cocaine, Glucose, and Dopamine, including DRD2, COMT, OPRD1, OPRM1, SLC6A3, CHRNA5, CNR1, CYP2C19, DBH, GABRA2, NOS1AP, and SYT1.

This in silico PGx analysis demonstrates strong, validated connections based on prior published data and robust computational predictions. Among the findings, the COMT gene was found to be the best-scoring gene here.

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.