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.