Current Neuropharmacology - Online First

Numerous studies have demonstrated that efgartigimod is effective in treating myasthenia gravis (MG) across various patient populations. However, there is limited evidence regarding its use in patients with new-onset acetylcholine receptor antibody-positive generalized MG (AChR-gMG). Therefore, this study aimed to investigate the real-world safety and effectiveness of efgartigimod in Chinese patients with new-onset anti-cholinergic receptor (AChR)- gMG.

This prospective study was conducted in 29 patients with new-onset AChR-gMG, with a three-month follow-up. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis score, prednisone dose, laboratory data, and adverse events were assessed at every follow-up visit.

At 4, 8, and 12 weeks, the mean change in MG-ADL scores was 8.13  ±  3.66, 7.41  ±  4.22, and 6.37  ±  4.67, respectively. Compared with the baseline, 96% (28/29) of patients achieved an MG-ADL response (defined as a decrease of ≥2 points), with a mean response time of 0.81 ± 0.53 weeks (5.67 ± 3.71 days). After one cycle, 52% (15/29) of patients achieved minimal symptom expression (MSE), while 41% maintained MSE at 12 weeks. Moreover, 89% and 72% of MG-ADL responders sustained for 8 and 12 consecutive weeks, respectively. Additionally, patients with thymomatous MG exhibited a poorer response to efgartigimod and required two infusion cycles. All patients were able to reduce their daily steroid dose, and the mean daily prednisone dose decreased by 10.73 mg per day. The treatment was well tolerated, and a few mild adverse events were reported.

These results demonstrate the clinical significance of efgartigimod in patients with new-onset AChR-gMG, achieving rapid symptom relief and steroid reduction. Additionally, the potential of efgartigimod to serve as a bridge treatment, facilitating a steady transition to long-term conventional immunosuppressive therapy, was demonstrated. Due to limitations in this study, such as a small sample size, larger randomized controlled trials are needed to validate.

Our study showed that efgartigimod is clinically beneficial and offers rapid symptom control in patients with new-onset AChR-gMG. A more aggressive application of efgartigimod in combination with corticosteroids may lead to a smoother therapeutic transition, which will further maintain favorable conditions.

Exogenous melatonin (exo-MLT) is a sleep-promoting agent that modulates key sleep-wake neurotransmitters.

This scoping review analyzed 623 studies retrieved from PubMed/MEDLINE and ISI/Web of Science, applying PRISMA methodology to ensure rigorous inclusion criteria. After screening, 58 original research papers were analyzed for exo-MLT's effects on gamma-aminobutyric acid (GABA), serotonin, dopamine, glutamine, norepinephrine, epinephrine, orexin, acetylcholine, adenosine, glycine, galanin, and histamine.

We identified 20 studies on the GABAergic system, showing that exo-MLT enhances GABA activity through different mechanisms, promoting non-REM sleep and reducing stress-related hyperarousal. On serotonin, 16 studies revealed limited and variable effects depending on the dose and physiological conditions. Total 13 dopamine studies suggested that exo-MLT does not alter physiological dopamine turnover, restoring dopaminergic balance in pathological states. On the glutamatergic system, seven studies showed a compensatory role of exo-MLT on glutamate excitotoxicity. Six studies on norepinephrine highlighted exo-MLT's ability to regulate sympathetic activity. The orexinergic system was the focus of five studies, indicating exo-MLT's inhibitory action on orexinergic neurons, enhancing sleep quality and consolidation. Five studies investigated exo-MLT on the cholinergic system, revealing an enhancing effect on acetylcholine activity in physiological and pathophysiological conditions. Lastly, four studies exploring adenosine and glycine were inconclusive of the exo-MLT effect, while we could not find any data on histamine and galanin.

This review underscores exo-MLT's mechanisms beyond circadian regulation, offering therapeutic promise in sleep disorders associated with other neuropsychiatric conditions.

Exo-MLT’s interactions provide insights into its safety and non-addictive characteristics, supporting its integration into personalized sleep medicine.

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.

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor, characterized by poor prognosis. Moreover, cognitive impairment from the tumor and its treatments compromises patients' quality of life. Butyrylcholinesterase (BChE) inhibition enhances cognitive function. Notably, BCHE is overexpressed in GBM tissues; its downregulation suppresses tumor cell proliferation, migration, and invasion. This study aimed to identify a BChE inhibitor with dual functionality: anti-GBM efficacy and cognitive protection via modulation of neuroinflammation.

QY-69 was identified from an in-house BChE inhibitor library through cytotoxicity-based screening. Its anti-GBM effects were evaluated through colony formation, wound healing, and transwell assays. Orthotopic GBM mice were treated with QY-69 orally for 15 days. Tumor progression, cognitive function (Morris water maze), and neuroinflammation (microglia and astrocyte immunofluorescence) were analyzed.

QY-69 exhibited significant antiproliferative activity at micromolar concentrations. In vitro assays demonstrated significant inhibition of GBM cell growth, migration, and invasion. Behavioral impairment in mice was improved, and the activation of astrocytes and microglia in peritumoral tissues was reduced, indicating a decrease in neuroinflammation.

QY-69 demonstrated dual therapeutic potential in GBM by inhibiting tumor progression and alleviating cognitive impairment. However, its precise molecular mechanisms remain to be elucidated. Future research should employ transcriptomic and proteomic approaches to elucidate the molecular basis of its anti-GBM activity.

QY-69, a BChE inhibitor, exhibits potent anti-GBM activity and confers cognitive protection, positioning it as a promising dual-action therapeutic candidate. By inhibiting tumor progression and reducing neuroinflammation, it may enhance both survival and quality of life in GBM patients.

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).

Advances in mass spectrometry-based proteomic analysis have generated extensive protein data from cells involved in neurodegenerative diseases. The field of neuroproteomics is expanding to include the study of extracellular vesicles (EVs) to identify potential biomarkers for disease prevention and endogenous factors involved in neuroprotection.

In this study, rat cortical astrocytes in normoxia were cultured under normoxic conditions and subsequently exposed to hypoxia. Astrocyte-derived EVs released into the supernatant were collected separately from both conditions. Label-free mass spectrometry-based proteomics was then performed to assess the effects of hypoxia on the EV protein cargo. A meta-analysis comparing the results with previously published EV proteomic datasets was also conducted.

This study revealed a differential expression of 83 upregulated proteins under hypoxic conditions and 61 downregulated proteins under normoxic conditions, highlighting the protective protein signatures elicited by astrocytes. The dataset has been deposited in the ProteomeXchange Consortium with the identified PXD050160.

The present study makes a novel contribution by employing proteomic techniques to characterize the protein cargo of EVs isolated from primary rat astrocytes. This approach enables a more refined analysis of astrocyte-specific intercellular signaling under hypoxic conditions and provides valuable insights into the roles of astrocytes in maintaining brain homeostasis and contributing to pathological processes.

Neurodegenerative diseases (NDDs) refer to a progressive degeneration of the nervous system and are on the rise. Researchers are trying to reveal the crucial mechanisms behind NDDs to find novel therapeutic candidates with higher efficacy and lower side effects. Increasing evidence highlights the auspicious role of inflammatory mechanisms in the pathogenesis of NDDs.

Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline, a systematic and comprehensive review was done to evaluate the effect of medicinal herbs in restoring gut-brain function and anti-inflammatory mechanisms in combating neuroprotection. The electronic databases, including Scopus, PubMed, and ScienceDirect, were searched for the literature review. The manual search of reference lists and citations was also employed falling within the authors’ expertise.

As with other mechanisms, the bidirectional communication between the brain and gut, known as the gut-brain axis, has emerged as a potential target for therapeutic interventions. Since the gut-brain axis covers multiple mechanisms, especially inflammatory mechanisms in NDDs, it urges the need for finding novel multi-targeting agents. Medicinal herbs, with their rich repertoire of natural products, are multi-targeting candidates in combating several diseases. In this systematic and comprehensive review, we explore the potential of medicinal herbs in restoring gut-brain function and promoting neuroprotection by suppressing inflammatory pathways. Novel delivery systems and clinical applications of medicinal herbs are also highlighted to drawback the pharmacokinetic limitation in regulating the gut-brain axis-associated NDDs.

Medicinal herbs provide neuroprotective responses through the modulation of gut-brain function and related inflammatory mediators.

Quercetin, a naturally occurring flavonoid, has been reported to possess several pharmacological activities including neuroprotective properties. Chronic alcohol exposure is known to cause apoptotic neurodegeneration. In this study, docking studies were used to investigate the ligand-protein affinity against various neuroinflammatory targets like ChAt, TNF, IL-6, and 
IL-1β. Next, molecular studies were performed to determine quercetin activity against chronic ethanol-induced neurodegeneration in the adult rat cortex.

Adult rats were treated with ethanol for 3 months while quercetin was treated for the last 20 days along with ethanol to the respective experimental groups. Elements of the mitochondrial apoptotic pathway i.e. pro-apoptotic protein Bax, cytochrome C release, and activation of caspase-9 and caspase-3 were determined after respective drug treatment. Our docking results revealed that quercetin possesses neuroprotective potential by targeting neuroinflammatory proteins inhibiting neurodegeneration.

Western blot results showed that ethanol administration increased the protein expressions of Bax, cytochrome C, caspase-9, and caspase-3. Furthermore, DNA damage was also observed by chronic ethanol treatment with increased expression of PARP-1. Quercetin treatment offered neuroprotection in the cortex against ethanol-induced neurodegeneration. Quercetin reversed the ethanol-induced apoptotic trend via down-regulating Bax, preventing cytochrome C release and inhibition of caspase cascade.

Immunohistological findings i.e. caspase-3 immunoreactivity, Nissl staining, and Fluoro-Jade B staining also revealed significant neuronal survival with quercetin treatment against ethanol-induced neuronal cell death. Our in-silico and in-vivo findings suggest that quercetin has the 
potential capability to be used as a neuroprotective agent against alcoholic neurotoxicity.

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.

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.

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.

This work aimed to develop a new and simple method to establish a mouse model of vascular dementia (VD). We investigated whether a new nitric oxide metabolite in the botanical mixture (a NO-donating botanical mixture, NOBM) improved learning and memory in mice that underwent bilateral carotid artery stenosis (BCAS).

C57BL/6N mice received the NOBM orally (0.1 mL twice a day) after BCAS, from days 1 to 28. We assessed spatial memory using the Y maze and place recognition tests at 1 week and 4 weeks after the induction of BCAS. We quantified the parvalbumin protein in the cortex and hippocampus at 1 week and 4 weeks. We also quantified expression levels of neuronal nuclei, brain-derived neurotrophic factor, glial fibrillary acidic protein, and the number of dead neurons performed Fluoro-Jade B staining 31 days after BCAS.

NOBM significantly improved learning and memory behaviour in BCAS mice. Immunohistochemistry staining and Western blotting data showed a significantly higher protein expression of parvalbumin in the cortex and hippocampus of NOBM-treated BCAS animals, especially in the early stage of BCAS. Moreover, NOBM reduces neuronal loss in the cortex and reduces neuroinflammation and oxidative stress. The observed effect suggests that the NOBM reduced the loss of parvalbumin inhibitory interneurons in the early stage of VD and inhibited neuroinflammation in the VD mice model.

Our results reveal a potential neuroprotective and therapeutic use of NOBM for cognitive dysfunction associated with cerebral hypoperfusion in a mouse model of VD.

Methcathinone, a synthetic cathinone derivative similar to amphetamine, has transitioned from a 1920s ephedrine precursor and Soviet-era antidepressant to a recreationally used substance since the 1970s-1980s, raising public health concerns due to its addiction potential and neurotoxicity-related health risks.

This review comprehensively analyzes methcathinone's impact on adult offspring, synthesizing recent advancements and critiquing literature to pinpoint key findings, challenges, and future research directions.

The systematic review adhered to PRISMA guidelines and encompassed case series, prospective and retrospective studies, as well as short communications published in English. An electronic search was conducted on PubMed, Elsevier, and CNKI. The focus was on methcathinone and its neuropsychological disorders and physical health complications, specifically in adult offspring.

A total of 8 studies met the inclusion criteria, resulting in a dataset of methcathinone on neurobehavioral and cognitive functions. These studies mainly found that prenatal methcathinone exposure in rats led to delayed physical development and induced anxiety-like behavior in offspring, with changes observed in neurobehavioral tests and the concentration of serotonin and dopamine. Furthermore, neurochemical effects were identified, showing dose- and time-dependent increases in extracellular dopamine and serotonin concentrations, and neurotoxic potential towards brain dopamine neurons.

This study concludes that methcathinone poses severe risks, including neurotoxicity for users and developmental harm for offspring, necessitating ongoing research to comprehend associated risks and inform public health interventions.