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.

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.