Current Neuropharmacology - Volume 23, Issue 2, 2025

This study investigates the connection between gut microbiota and poisoning caused by narcotics and psychodysleptics, using Mendelian randomization (MR) to explore possible causal relationships.

The study employed the MR analysis, leveraging genetic variants as instrumental variables to facilitate robust causal inference. Data for gut microbiota was extracted from the MiBioGen study, integrating genome-wide genotyping data with 16S fecal microbiota profiles. Outcome metrics were based on the Finngen study. Genetic instruments were meticulously extracted based on stringent criteria, and harmonized with SNP outcomes associated with “Poisoning by narcotics and psychodysleptics (hallucinogens)”. The inverse-variance weighted (IVW) method was utilized for MR analysis, supplemented by sensitivity analyses including MR-Egger Regression, Weighted Median Approach, and Leave-One-Out Cross-Validation.

Among various microbial groups, nine showed significant statistical links. Specifically, Class Negativicutes (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) and Order Selenomonadales (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) were notably associated. These findings were consistent across different sensitivity analyses.

The relationship between gut microbiota and the adverse effects of narcotics and psychodysleptics is an emerging area of research. Our MR study identifies certain microbes that might influence the body's response to these substances. These insights could help in predicting and treating the effects of narcotics and psychodysleptics in the future.

Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) post-challenge. The potential link between VTX and NLRP3, along with other inflammasomes, remains 
un-explored.

The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD.

Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was demonstrated that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway.

Thus, a novel VTX molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.

The identification of specific circulating miRNAs has been proposed as a valuable tool for elucidating the pathophysiology of brain damage or injury and predicting patient outcomes.

This study aims to apply several bioinformatic tools in order to clarify miRNA interactions with potential genes involved in brain injury, emphasizing the need of using a computational approach to determine the most likely correlations between miRNAs and target genes. Specifically, this study centers on elucidating the roles of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a.

After a careful evaluation of different software available (analyzing the strengths and limitations), we applied three tools, one to perform an analysis of the validated targets (miRTarBase), and two to evaluate functional annotations (miRBase and TAM 2.0).

Research findings indicate elevated levels of miR-135a and miR-34b in patients with traumatic brain injury (TBI) within the first day post-injury, while miR-200c and miR-34c were found to be upregulated after 7 days. Moreover, miR-451a and miR-135a were found overexpressed in the serum, while miRNAs 34b, 34c, and 200c, had lower serum levels at baseline post brain injury.

This study emphasizes the use of computational methods in determining the most likely relationships between miRNAs and target genes by investigating several bioinformatic techniques to elucidate miRNA interactions with potential genes. Specifically, this study focuses on the functions of miR-34b, miR-34c, miR-135a, miR-200c, and miR-451a, providing an up-to-date overview and suggesting future research directions for identifying theranomiRNAs related to brain injury, both at the tissue and serum levels.

Growing evidence suggests that repeated-dose intravenous ketamine in patients with depression had rapid antianhedonic effects. However, a comparison of the antianhedonic effects of repeated-dose intravenous ketamine between younger adults and older depressed patients has not been examined.

To the best of my knowledge, this study with a total of 135 patients with major depressive episodes (MDE) is the first to compare the antianhedonic effects between younger adult (n = 116) and older (n = 19) depressed patients receiving six ketamine infusions (0.5 mg/kg over 40 min). Montgomery-Åsberg Depression Rating Scale (MADRS) was applied in this study to evaluate the clinical symptoms, and MADRS anhedonia item scoring was used to evaluate anhedonia symptoms.

Patients received six open-label intravenous infusions of ketamine for 12 days. MADRS anhedonia subscale scores decreased in both younger (3.3, 95% CI = 2.5-4.1, p < 0.05) and older (2.8, 95% CI = 1.1-4.6, p < 0.05) MDE patients at 4h after the first infusion compared to baseline scores and the reduction was maintained over the subsequent infusion period in both groups (all Ps < 0.05). Younger MDE patients had lower MADRS anhedonia subscale scores on day 26 compared with older patients (P = 0.02). Compared with younger adult MDE patients, older patients had a lower antianhedonic response (51.7% [95% CI = 42.5%-61.0%] versus 31.6% [95% CI = 8.6%-54.6%)] and remission (24.1% [95% CI = 16.2%-32.0%] versus 0%).

This study indicates that repeated-dose intravenous ketamine administration induces rapid and robust antianhedonic effects in older MDE patients. However, older MDE patients displayed less response to ketamine than younger adult MDE patients.

ChicCTR-OOC-17012239.