Current Neuropharmacology - Online First

This study investigates the relationship between National Cancer Institute Common Terminology Criteria (NCI-CTC) for grading bortezomib-induced peripheral neuropathy (BIPN) and objective motor/sensory nerve dysfunctions assessed by nerve conduction studies (NCS). It also evaluates the correlation between specific nerve conduction abnormalities and progression-free survival (PFS).

Thirty-three patients with multiple myeloma developing peripheral neuropathy during bortezomib treatment were enrolled. Participants were grouped based on NCI-CTC toxicity scores (< 2, n=17; ≥ 2, n=16). Comprehensive NCS were performed, assessing compound muscle action potentials (CMAP), motor conduction velocities (MCV), sensory nerve action potentials (SNAP), and sensory conduction velocities (SCV) across ulnar, median, tibial, peroneal, sural, and superficial peroneal nerves. Correlation analyses were used to examine the association between NCS parameters and PFS.

Patients with higher NCI-CTC grades (≥ 2) exhibited significant reductions in motor and sensory nerve conduction parameters. Notably, the peroneal nerve showed significant decreases in CMAP (p=0.0059) and MCV (p=0.0223). The superficial peroneal nerve displayed a significant reduction in SCV (p=0.0189). A strong positive correlation was found between median nerve SNAP and longer PFS (r=0.558, p=0.001).

The findings indicate that higher clinical grades of BIPN (NCI-CTC ≥ 2) are associated with objective neurophysiological evidence of worsened nerve function, with the peroneal nerve being particularly affected. The correlation between median nerve SNAP and PFS suggests that NCS parameters could potentially serve as prognostic markers in patients with BIPN.

Bortezomib-induced neurotoxicity leads to significant impairments in both motor and sensory nerve conduction. Median nerve SNAP shows promise as a predictor for PFS, underscoring the potential value of NCS in monitoring neurotoxicity and guiding clinical management in patients receiving bortezomib.

Multiple Sclerosis (MS) is characterized by the infiltration of leukocytes into the nervous tissue, and disruption of the Blood-Brain Barrier (BBB) is one of the main factors in the progression of MS and its model, Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, some anti-lymphocytic drugs against MS may inherently produce BBB disruption as their side effect. This study hypothesized that drugs restoring the BBB may be useful for the treatment of MS and EAE, as well as for ameliorating the side effects of modern anti-lymphocytic drugs.

EAE was induced in SJL/J mice. EAE progression was evaluated by a severity score and a plasma cytokine profile, while a BBB condition was evaluated by the Evans dye method, Tight Junction Proteins (TJPs) content, and leukocyte infiltration.

The mice with EAE demonstrated neurological symptoms, a cytokine response, and BBB deterioration, which was associated with upregulation of the NADPH oxidases NOX1 and NOX4 in the brain. Administration of the anti-lymphocyte drug fingolimod to EAE mice caused lymphopenia, improved animal health, enhanced the BBB function during the administration period, and decreased the pro-inflammatory response, but it was accompanied by a “withdrawal effect,” defined as a sharp increase in the IL-17 and IFN-gamma to levels higher than those in untreated animals, lymphocyte hyperactivation, worsening symptoms, and increasing BBB permeability after discontinuation of fingolimod. Administration of peroxiredoxin 6 (Prdx6) to EAE mice also improved BBB, decreased lymphocyte infiltration and NADPH oxidase expression, and ameliorated symptoms. Preliminary administration of Prdx6 before the fingolimod treatment eliminated the “withdrawal effect” of fingolimod and led to full recovery of the EAE mice. This Prdx6 effect was associated with the activation of anti-proliferative and pro-apoptotic signaling cascades in lymphocytes.

Conclusion: Both fingolimod and Prdx6 produced beneficial effects, while Prdx6 may be useful for ameliorating the side effects of anti-lymphocytic drugs. Accounting for literature data that discontinuation of MS treatment is very likely to lead to a severe MS rebound, a drug that prevents the rebound should be useful.

Maternal chronic immune and inflammatory conditions may predispose newborns to atypical developmental trajectories, identifying pregnancy as a key period for the etiopathogenesis of neurodevelopmental disorders. The possible long-term impact of maternal multiple sclerosis (MS) on the offspring’s cognitive and behavioral development and its pharmacological treatment during pregnancy is mostly unknown. This study aims to delineate the cognitive and behavioral profile of offsprings exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, in comparison to a control group.

We retrospectively enrolled 39 children (23 males; 16 females; mean age 45.82 ± 35.46 months) exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, and 36 children (24 males; 12 females, mean age 38.03 ± 21.52 months) of healthy mothers. All offspring underwent a standardized evaluation of their intellectual or developmental quotient, adaptive functioning, and behavioral issues, including symptoms of autism.

The clinical profile of the included offspring was characterized by an adequate cognitive profile and a good level of adaptive skills (MS offspring: Griffiths III mean total DQ (N = 30) 114.57; WISC-IV mean Full IQs (N= 9) 115.44; mean ABAS GAC 97.28/Control offspring: Griffiths III mean total DQ (N = 31) 105.42; WISC-IV mean Full IQs (N= 4) 119.25 ± 11.32; mean ABAS GAC 97.82 ± 21.4). Furthermore, no significant behavioural problems or autism symptoms emerged in the entire group, regardless of MS treatment.

Offspring's developmental and behavioral phenotypes do not appear to be influenced by maternal treatment with Natalizumab until late pregnancy, nor by maternal variables directly related to MS (age at the time of MS diagnosis, disease duration, and severity).

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.

In the medicinal chemistry (MC) field, artificial intelligence (AI) has been used to establish quantitative structure-activity relationship (QSAR) classification models, virtual screening, drug discovery, drug design, and so on. In this investigation, MC AI studies (AI-MC) (from 2001-2023) underwent quantitative and qualitative modeling analyses.

Using a hybrid research strategy incorporating content analyses and bibliometric methods, we retrospectively analysed the AI-MC literature using a bibliometrix package (R software) combined with CiteSpace V and VOSviewer programs.

Between 2001 and 2023, AI-MC articles were published in 92 countries or regions, with China and the United States leading in the number of publications. Also, 196 affiliations were added to AI-MC research; the CHINESE ACADEMY OF SCIENCES contributed the most. Reference clusters were categorized as follows: (1) QSAR, (2) virtual screening, (3) drug discovery, (4) drug design. Predictive model (2020-2021), molecular fingerprints (2021-2023) and scoring function (2021-2023) reflected research frontier keywords. As we look to the future, the ongoing progress and innovation in technology herald the promising development of multimodal and large language models (LLMs) within the realm of MC.

The integration of AI into MC has significantly transformed the landscape of drug development. AI techniques, particularly machine learning, and deep learning algorithms, have demonstrated remarkable potential in accelerating the discovery and optimization of new drugs. By leveraging large datasets and advanced computational models, AI enhances the efficiency of virtual screening, improves the accuracy of QSAR models, and facilitates the design of novel therapeutic agents. As the technology continues to advance, the development of multimodal and large language models (LLMs) is expected to further revolutionize this field, offering new opportunities for more precise and efficient drug design and discovery.

We comprehensively characterized the AI-MC field and determined future trends and hotspots. Importantly, we provided a dynamic oversight of the AI-MC literature and identified key upcoming research areas.

High-altitude cerebral edema (HACE) is a serious condition caused by prolonged hypobaric hypoxia (HH). Autophagic degradation of Claudin-5 plays a crucial role in HH-induced blood-brain barrier (BBB) damage. Hydroxychloroquine (HCQ), a lysosomal inhibitor used in autophagy treatment, reduces inflammation and BBB damage in traumatic brain injury. However, its effectiveness in preventing HACE is still unknown.

C57BL/6J mice were treated with HCQ and exposed to HH for 24 hrs to study BBB integrity. We evaluated BBB disruption via brain water content, Evans blue, and FITC-dextran assays. Changes in tight junctions (TJs) of cerebrovascular endothelial cells were analyzed using electron microscopy and immunofluorescence. Western blotting quantified autophagy protein levels in brain tissue. Hypoxia-mimetic in vitro models were used to explore HCQ's effects on TJs and BBB permeability, confirmed by various assays, including immunofluorescence, electron microscopy, and Western blotting.

HCQ significantly mitigated rapamycin-induced autophagy and Claudin-5 degradation. Prolonged hypoxia exposure promoted lysosomal degradation of Claudin-5, increasing endothelial cell permeability. HCQ inhibited autophagy in bEnd.3 cells via the PI3K-Akt-mTOR and Erk pathway, reducing hypoxia-induced Claudin-5 down-regulation. In mice, HH exposure increased brain autophagy, damaging the vascular endothelial TJs and subsequently increasing endothelial permeability. Pretreatment with HCQ significantly reduced the level of autophagy in the brains of HH-exposed mice, thereby mitigating the HH-induced damage to vascular TJs, alleviating the downregulation of Claudin-5, and enhancing endothelial integrity.

HCQ effectively prevented HACE by inhibiting HH-induced Claudin-5 membrane expression downregulation, thus mitigating BBB damage and brain water content increase in HH-exposed mice.

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.