Current Neuropharmacology - Online First

The growing prevalence of neuropsychiatric disorders is becoming a major health challenge. Traditional pharmacotherapies face limitations, making drug repurposing a valuable strategy. However, high-throughput screening approaches for these conditions are scarce.

This study leveraged exposure data from the UK Biobank Neale Lab (N = 361,141) and outcome data from the FinnGen database (N = approximately 410,000) to employ Mendelian Randomization (MR) analyses and identify potential drug repurposing candidates for neuropsychiatric disorders. Sensitivity, Linkage Disequilibrium Score Correlation (LDSC), and Bayesian Colocalization (COLOC) analyses were conducted to ensure the robustness and reliability of our findings.

Using the IVW method, seven medications with negative causal associations with neuropsychiatric disorders were identified. Pregabalin, bumetanide, and prednisolone were associated with reduced anxiety (beta = -7.28, p = 4.00e-03; beta = -2.24, p = 6.00e-03; beta = -1.74, p = 2.84e-03). Vitamin B1 preparations showed an inverse association with dementia (beta = -2.47, p = 1.51e-03), Creon E/C granules with epilepsy (beta = -4.99, p = 3.91e-03), Pentasa SR 250 mg with multiple sclerosis (beta = -3.95, p = 3.83e-03), and zolmitriptan with stroke excluding subarachnoid hemorrhage (beta = -1.61, p = 6.00e-03). Sensitivity analyses confirmed these findings, whereas the LDSC and COLOC analyses provided additional support.

MR-based drug repurposing is a promising approach for the treatment of neuropsychiatric disorders. Further validation is necessary to effectively integrate these medications into clinical practice.

Parkinson’s disease (PD) is often associated with depression, which poses an additional burden for patients and their families. However, evidence regarding the optimal treatment for depression in PD remains limited, with insufficient data supporting the efficacy of most antidepressant drugs.

The primary objective of this pilot, prospective, open-label, single-arm study was to analyze the safety and tolerability of vortioxetine drops on depressive symptoms in PD patients over 16 weeks of treatment. The secondary objective was to study vortioxetine's effectiveness on depression.

Sixteen out of 20 PD patients who completed the study demonstrated that the treatment was safe and well tolerated; no change in PD symptom severity, abnormality of clinical parameters, body weight, or ECG emerged. The most common side effect was nausea. Depressive symptoms rated by the Beck Depression Inventory and the Hamilton Depression Rating Scale score (HAM-D-17) showed a significant improvement at the end of the study period without a worsening of motor functions, as measured by UPDRS part III. The majority of patients also reported an improvement in depressive symptoms measured by the Patient Global Impression of Improvement scale.

Vortioxetine is a safe and well-tolerated therapeutic approach for depression in Parkinson’s disease. As a secondary objective, an improvement in depressive symptoms was observed. However, the study’s open-label design and small sample size limit the generalizability of the findings.

NCT04301492.

Polyglutamine (polyQ) spinocerebellar ataxias (SCA) are a group of autosomal dominant neurodegenerative disorders for which no effective treatments currently exist. These conditions impose a significant burden on patients, their families, and society. Consequently, the treatment of these disorders has attracted significant global interest.

We conducted this bibliometric analysis to identify the key research hotspots and predict the future research directions of this field.

Studies relating to the treatment of polyQ SCA published from 1999 to 2024 were retrieved from the Web of Science Core Collection database. Relevant papers were selected using predefined inclusion and exclusion criteria. HistCite, VOSviewer, CiteSpace, and alluvial generator were used in the bibliometric analysis.

Overall, 935 papers were included. The number of publications in this field showed a trend toward a fluctuating increase. The United States and the University of Coimbra were the leading countries and institutions, respectively, in terms of publication number. The two most productive and highly cited authors were Luis Pereira de Almeida and Patricia Maciel. The journals Cerebellum, Human Molecular Genetics, and Movement Disorders were considered the most influential based on the number of publications and citations. Furthermore, “new SCA types”, “Huntington’s disease”, “clinical trial”, “gene therapy”, “disease models,” and “Aggregation clearance therapy” emerged as current hotspots in this field, as revealed by the reference and keyword analyses.

This study presents a systematic bibliometric analysis of research on the polyQ SCA treatment, which we hope will assist researchers in identifying the key topics and future research directions in this field.

Radiotherapy is one of the main therapeutic methods for tumors, and radiation-related cognitive impairment has attracted increasing attention. The purpose of this study was to explore the research prospects in the field of radiotherapy-associated cognitive decline through bibliometric analysis.

Literature on radiotherapy-related cognitive impairment published during 2004-2023 were extracted from the Web of Science Core Collection database. VOSviewer and R-bibliometrix were utilized to perform bibliometric analysis.

A total of 8,365 publications were retrieved from the database. The United States emerged as the leading country in this research field, with St. Jude Children's Research Hospital identified as the most productive institution. Thomas E. Merchant was the most prolific author in this field, while Charles L. Limoli was the most frequently cited scholar. The research hotspots have gradually shifted from cognitive function and outcome measurement to the development of new therapy models.

This study comprehensively examined the research hotspots and knowledge atlas of radiotherapy-related cognitive decline from a bibliometric perspective. Our results would assist scholars in identifying potential collaborators and significant literature in this field while also providing valuable guidance for future research directions.

Neurotoxicity is the severe adverse reaction induced by chemotherapy drugs, characterized by neuropathic pain. However, there is a notable lack of therapeutic drugs for chemotherapy-induced neuropathic pain (CINP). Celastrol, a naturally occurring terpenoid active compound extracted from the roots of Tripterygium wilfordii Hook f., exhibits a neuroprotective effect, yet its therapeutic potential in CINP has not been reported.

In this study, with vincristine-induced neuropathic pain (VINP) as a model, we aimed to investigate the therapeutic effect of celastrol on VINP and its specific mechanisms.

Vincristine (VCR, 0.1 mg/kg, intraperitoneal injection) was used to induce a neuropathic pain model. Celastrol (0.5, 1.0, and 2.0 mg/kg, intraperitoneal injection) was administered to assess its therapeutic effects on VINP. Transmission electron microscopy (TEM) was employed to examine damage to the sciatic nerve fibers and mitochondria. Flow cytometry was used to detect mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and cell apoptosis. Primary astrocyte cultures were utilized further to validate the therapeutic mechanisms of celastrol in VINP.

Here, we demonstrate that celastrol inhibits VCR-induced activation of spinal astrocytes by suppressing CaMKII phosphorylation. Additionally, celastrol alleviates the Cx43-dependent inflammation caused by VCR through the inhibition of the CaMKII/NF-κB signaling pathway. Concurrently, celastrol modulates the production of reactive oxygen species (ROS) and the expression of apoptosis-related proteins (Cleaved Caspase-3, Bax, and Bcl-2) by suppressing the phosphorylation of CaMKII in astrocytes, thereby ameliorating the mitochondrial damage and cell apoptosis caused by VCR.

This study delves into the efficacy of celastrol in treating VINP and elucidates its underlying mechanisms. The findings demonstrate that celastrol elevates pain thresholds in mice, ameliorates neuropathy, and inhibits VCR-induced astrocyte activation, as well as spinal dorsal horn inflammation, oxidative stress, and apoptosis, by blocking CaMKII phosphorylation. Unlike first-line CINP drugs, celastrol targets multiple CINP-related pathological pathways. However, this study primarily focuses on male mice and lacks a naive group, which may affect the interpretation of baseline physiological parameters. Therefore, future research will incorporate female mice and naive groups to further enhance the study's comprehensiveness and reliability.

Our findings reveal that celastrol exerts therapeutic effects on VINP through its anti-inflammatory, antioxidant, and anti-apoptotic properties. Furthermore, we preliminarily explore the molecular mechanisms underlying these effects, thereby providing a scientific basis for celastrol as a potential therapeutic agent for CINP.