CNS & neurological disorders drug targets最新文献

Autism Spectrum Disorder (ASD) constitutes a group of neurodevelopmental disorders characterized by impairments in verbal and nonverbal communication skills, social interactions, and stereotypes of behavior, with an estimated frequency of 1.2% of children throughout the world. The lack of specific treatments or molecular biomarkers underscores the complexities of ASD as a nonunified clinical entity. Comorbid medical conditions are particularly associated with gastrointestinal issues that may suggest potential interactions between the brain and gut. This review suggests that serotonin plays a significant role in the enteric and central nervous systems in relation to ASD. The modulatory role of serotonin in the enteric nervous system is examined in relation to the pathophysiology of ASD in order to shed light on prospective biomarkers and therapeutic targets that could increase the precision of diagnosis and treatment.

Brain ischemia-reperfusion injury (CIRI) refers to brain ischemia that leads to cellular dysfunction and cell death after a certain period, and ischemic damage is rescued by providing blood supply and reperfusion. And then, reperfusion includes components such as ion imbalance, mitochondrial dysfunction, oxidative stress, neuroinflammation, Ca²⁺ overload, and apoptosis, which do not cause tissue damage. Autophagy also occurs in CIRI due to oxygen deficiency, and autophagy has been shown to protect cells from ischemic injury. Flavonoids are a class of essential and diversified secondary plant metabolites found in different concentrations in leaves, flowers, roots, and fruits. Various studies have shown that flavonoids have healing qualifications such as anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial. We aim to determine how flavonoids may affect signaling pathways and kinases in rats with CIRI. The results show that the activity of JAK2/STAT3, NF-κB, RhoA/ROCK, JNK-p38, and cAMKII signaling pathways increases under CIRI, and the PI3K/Akt/mTOR signaling pathway is suppressed. Studies using various flavonoids (kaempferol, chrysin, naringin, naringenin, quercetin, wogonin) have shown a neuroprotective effect by reversing the situation in signaling pathways during CIRI damage.

Alzheimer's Disease (AD) is a neurodegenerative disorder mainly characterized by dementia and cognitive decline. AD is essentially associated with the presence of aggregates of the amyloid-β peptide and the hyperphosphorylated microtubule-associated protein tau. The available AD therapies can only alleviate the symptoms; therefore, the development of natural treatments that exhibit neuroprotective effects and correct the behavioral impairment is a critical requirement. The present review aims to collect the natural substances that have been evaluated for their neuroprotective profile against AD-like behaviors induced in zebrafish (Danio rerio) by scopolamine. We focused on articles retrieved from the PubMed database via preset searching strings from 2010 to 2023. Our review assembled 21 studies that elucidated the activities of 28 various natural substances, including bioactive compounds, extracts, fractions, commercial compounds, and essential oils. The listed compounds enhanced cognition and showed several mechanisms of action, namely antioxidant potential, acetylcholinesterase's inhibition, and reduction of lipid peroxidation. Additional studies should be achieved to demonstrate their preventive and therapeutic activities in cellular and rodent models. Further clinical trials would be extremely solicited to support more insight into the neuroprotective effects of the most promising drugs in an AD context.

Background: A major issue with neurodegenerative diseases is cholinergic depletion, the development of oxidative stress, and the reduction in the ability to control the expression of genes involved in the regulation of neurogenesis. The most widespread neurodegenerative disease is Alzheimer's disease (AD). Current treatments are not able to improve the symptoms of the disease. Thus, selecting or creating a safe and effective drug is very important.

Objective: In this context, the potential of sweroside (Swe) to regulate acetylcholinesterase (AChE) activity, malondialdehyde (MDA) level, and bdnf, npy, egr1, nfr2a, and creb1 gene expression in the scopolamine (Sco)-induced zebrafish model of cognitive impairment was investigated.

Methods: Swe was administered daily for 16 days chronically to zebrafish at concentrations of 1 μg/L, 3 μg/L, and 5 μg/L whereas Sco (100 μM) was given to zebrafish for 30 min.

Results: Exposure to Swe decreased AChE activity and MDA level along with upregulating of gene expression in the brain of the Sco-induced zebrafish model.

Conclusion: Overall, our findings suggested that Swe has a positive role in the cholinergic system activity and brain antioxidant status and showed for the first time that it can restore the downregulated expression of bdnf, npy, egr1, nfr2a, and creb1 genes in the brain of the Sco-induced zebrafish model.

Alzheimer's disease (AD) is the primary cause of dementia in elderly individuals, characterized by progressive memory loss, cognitive decline, and impaired daily functioning. Pathologically, AD is associated with the accumulation of amyloid-β (Aβ) plaques, tau tangles, mitochondrial dysfunction, and chronic neuroinflammation. The activation of the NOD-like receptor pyrin domain- containing 3 (NLRP3) inflammasome by Aβ clusters triggers microglial activation, leading to a cascade of inflammatory responses. Similarly, tau tangles stimulate neuronal and glial cells, further amplifying NLRP3 activation and perpetuating a cycle of chronic inflammation. Mitochondrial dysfunction exacerbates this process by increasing oxidative stress and inflammasome activation. Additionally, purinergic receptor P2X7 (P2X7R) activation in microglia plays a crucial role in initiating neuroinflammation, making it a potential therapeutic target. Despite extensive research, current AD therapies remain symptomatic rather than disease-modifying. Targeting the NLRP3 inflammasome offers a promising strategy for mitigating AD progression. Various small-molecule inhibitors, monoclonal antibodies, and repurposed drugs have been explored to inhibit NLRP3 activation and its downstream signaling pathways. Preclinical studies suggest that NLRP3 inhibitors effectively reduce Aβ- and tau-induced neuroinflammation while improving mitochondrial function and overall neuronal survival. This review summarizes NLRP3 inflammasome priming, activation, and the therapeutic potential of its inhibitors in AD, highlighting challenges such as tau pathology, biomarker limitations, and treatment optimization. While NLRP3 remains a promising target, most inhibitors are in the early stages with uncertain long-term efficacy and BBB penetration. Future research should explore genetic variability, sex differences, and alternative approaches to enhance neuroprotective strategies.

Parkinson's disease is a neurodegenerative condition characterized by slow movement (bradykinesia), tremors, and muscle stiffness. These symptoms occur due to the degeneration of dopamine- producing neurons in the substantia nigra region of the brain, leading to reduced dopamine levels. The development of Parkinson's Disease (PD) involves a combination of genetic and environmental factors. PD is associated with abnormal regulation of the monoamine oxidase (MAO) enzyme. Monoamine oxidase inhibitors (MAOIs) are an important class of drugs used to treat PD and other neurological disorders. In the early stages of PD, monotherapy with MAO-B inhibitors has been shown to be both safe and effective. These inhibitors are also commonly used as adjuncts in long-term disease management, as they can improve both motor and non-motor symptoms, reduce "OFF" periods, and potentially slow disease progression. However, current MAO-B inhibitors come with side effects like dizziness, nausea, vomiting, light-headedness, and fainting. Therefore, accelerating the development of new MAO-B inhibitors with fewer side effects is crucial. This review explores natural compounds that may inhibit monoamine oxidase B (MAO-B), focusing on key findings from the past seven years. It highlights the most effective heterocyclic compounds against MAO-B, including thiazolyl hydrazone, pyridoxine-resveratrol, pyridazine, isoxazole, oxadiazole, benzothiazole, benzoxazole, coumarin, caffeine, pyrazoline, piperazine, piperidine, pyrrolidine, and morpholine derivatives. The review covers in vitro, in silico, and in vivo data, along with the structure- activity relationship of these compounds. These findings offer valuable insights for the development of more effective MAO-B inhibitors and advancements in Parkinson's disease research.

Background: Botulinum Toxin type A (BonTA) is the preferred treatment for Cervical Dystonia (CD). However, the success rate is often suboptimal. One of the reasons for treatment failure is the inaccuracy of injections. Some physicians rely on Anatomical Landmarks (AL) for injections, while others use either Ultrasound (US) or Electromyography guidance (EMGg) to improve accuracy.

Methods: This retrospective two-center study compared the therapeutic outcomes of AL-based and EMGg injections with USg injections. Demographic and clinical assessments of previous visits and current visits were recorded between 2019 and 2023.

Results: Fifty-one patients were included. Six patients were injected using AL, 14 patients under EMGg, and 31 patients received USg injections. Pain relief was significantly lower for the AL group (40.0% ± 22.4%) compared to both USg and EMGg (81.2% ± 34.0% and 82.2% ± 10.3%, respectively; p = 0.001). Dysphagia was reported in 7.1% of EMGg and 16% of the USg group and none of those treated with AL (p > 0.05).

Conclusion: The results of this study demonstrated that the clinical outcomes of USg and EMGg BonTA injections are comparable and both techniques are superior to AL. The main side effect observed was dysphagia, which was more common in the USg group, although without reaching statistical significance.

A recent World Health Organization report claims that along with the growing world population and emerging life prospects, the prevalence of neurological disorders is also increasing. Out of all neurological disorders, Alzheimer's disease is the most widespread and alarming concern. The disease poses significant therapeutic challenges due to the blood-brain barrier's restrictiveness and the lack of effective drug delivery systems. The olfactory and trigeminal nerves have direct access to the brain, therefore, intranasal drug delivery can be a promising route for the direct delivery of anti-Alzheimer's drugs. Despite this advantage, brain targeting is limited through this route due to mucociliary clearance. Thus, in situ, nanotechnology offers a transformative approach by leveraging the intranasal route to directly target the central nervous system. This comprehensive review discusses recent advancements, mechanisms, and applications of in situ nanotechnology in Alzheimer's disease therapeutics, highlighting its potential to enhance drug delivery efficiency, improve bioavailability, and mitigate the progression of this debilitating condition. The importance of intranasal drug delivery has been emphasized in this review, along with the clear benefits of in situ lipid- based nanotechnology for the efficient delivery of medication in targeting Alzheimer's disease.

The most common neurodegenerative illness and leading cause of death in the world is Alzheimer's disease (AD), which is extremely expensive to treat. None of the AD treatments that are currently in the market with approval have any effect on disease progression. However, numerous clinical studies aimed at reducing amyloid beta (Aβ) plaque development, boosting Aβ clearance, or reducing neurofibrillary tangle (NFT) failed or had conflicting results. As oxidative stress (OS), mitochondrial dysfunction, and chronic neuroinflammation are implicated in numerous interconnected vicious cascades, research has revealed new therapeutic targets, including enhancing mitochondrial bioenergetics and quality control, reducing oxidative stress, or modulating neuroinflammatory pathways. This review examines the role of oxidative stress (OS), mitochondrial dysfunction, neuroinflammation, and the interplay between peripheral and central immune systems in the pathogenesis of AD. We highlight how OS and immune dysregulation drive chronic neuroinflammation, exacerbating AD progression. Immune cells and inflammatory molecules emerge as critical players in disease pathology. Overall, this review concludes that targeting OS and immune system crosstalk represents promising therapeutic strategies for mitigating AD progression, providing a foundation for future interventions.

Introduction: Gantenerumab (GR), a promising therapeutic agent for Alzheimer's disease (AD), has been the subject of extensive research. In this study, we aimed to provide a comprehensive analysis of the literature on GR.

Methods: A systematic search was conducted using the PubMed, Scopus, and Web of Science databases. VOSviewer and Bibliometrix were utilized to analyze bibliographic data.

Results: The analysis of the literature on GR revealed distinct publication trends. Reviews accounted for 52% of the records, followed by research articles (31%). The United States contributed the highest proportion of publications (26%). The Journal of Prevention of Alzheimer's Disease was the most prolific source (21 articles). The annual number of publications increased steadily from 2009 to 2024. Major international collaborations were observed among the United States, the United Kingdom, Switzerland, France, and Sweden. Research activity consistently centered on key themes, such as amyloid imaging, biomarkers, clinical trials, and β-amyloid. Thematic mapping identified specialized subfields, core research areas, and dynamic shifts in topics, offering a comprehensive overview of the GR research landscape.

Conclusion: GR-related literature showed sustained thematic focus, growing international collaboration, and a steady rise in publication volume within the field of AD. These findings highlight the continued need for clinical and biomarker-focused investigations to advance therapeutic development in AD.