CNS & neurological disorders drug targets最新文献

Introduction: Epilepsy is a common neurological disorder managed with anti-epileptic drugs (AEDs), which often cause side effects and limited efficacy. This study aims to evaluate a novel series of 1,2,4-triazine fused thiazolidin-4-one derivatives for their anticonvulsant and antioxidant potential as safer and more effective therapeutic options.

Methods: Twelve 1,2,4-triazine fused thiazolidin-4-one derivatives (HRSP1-HRSP12) were synthesized. Anticonvulsant activity was assessed using the maximal electroshock (MES) model, while antioxidant potential was evaluated through DPPH and FRAP assays. Cortical GABA and glutamate levels were quantified in mice. Safety was evaluated via acute toxicity studies. In silico studies included molecular docking, induced fit docking, MM-GBSA, and molecular dynamics simulations to assess GABAA receptor interactions.

Results: HRSP8 showed the strongest anticonvulsant activity among the synthesized compounds, reducing hind limb tonic extension (HLTE) to 7.91 ± 0.25 s (30 mg/kg) and 6.89 ± 0.09 s (100 mg/kg), comparable to standard drugs (phenytoin and carbamazepine). It exhibited an ED50 of 27.49 mg/kg, TD50 >565 mg/kg, and a protective index >20.51. HRSP8 also increased cortical GABA and decreased glutamate levels. Antioxidant assays confirmed strong radical scavenging activity. Docking (-7.80 kcal/mol) and MM-GBSA (-82.42 kcal/mol) suggested high GABAA receptor affinity, supported by stable molecular dynamics.

Discussion: HRSP8's effects appear to involve GABAA receptor modulation and neurochemical balance restoration, with additional antioxidant support. Its safety margin and stable receptor binding indicate therapeutic promise. These results align with existing GABAergic strategies in epilepsy. Further validation in chronic models and pharmacokinetic studies is needed.

Conclusion: HRSP8 demonstrated notable anticonvulsant and antioxidant activities, a wide safety margin, and strong affinity for the GABAA receptor. These findings support its potential as a lead compound for further preclinical evaluation in epilepsy therapy.

Introduction: Neuroinflammation is a key pathological process in neurological disorders, from acute injuries to chronic diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke. The mTOR pathway regulates neuroinflammation by influencing microglial activation, autophagy, and synaptic plasticity. To address the scarcity of systematic analyses in this growing field, our study employs bibliometric analysis to map the landscape, identify key themes and collaborations, and highlight therapeutic targets for future neurological research.

Methods: A Web of Science search retrieved articles published up to 2024. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace, Charticulator, and Microsoft Excel.

Results: A total of 509 articles were examined, showing a fluctuating increase in publications and citations. China had the highest output, and the Journal of Neuroinflammation was the most active journal. Mehan Sidharth emerged as a leading researcher. The most cited study was "HIF1α- dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells". Findings revealed strong links between neuroinflammation and AD, PD, and stroke, and highlighted mTOR inhibitors as promising therapeutic agents.

Discussion: Our analysis identified highly-cited works, current trends, emerging frontiers, and the significance of mTOR inhibitors. However, the comprehensiveness of our bibliometric approach may have been limited by the field's vast scope and by analytical disparities between CiteSpace and VOSviewer, potentially resulting in omissions.

Conclusion: This study provides an overview of scientific progress on mTOR signaling and neuroinflammation, emphasizing its key role in disease mechanisms and suggesting directions for therapeutic innovation.

Aneurysmal Subarachnoid Hemorrhage (SAH) is a devastating cerebrovascular event with high morbidity and mortality rates, and early brain injury following SAH (EBI-SAH) within 72 h leads to a poor prognosis. Despite advances in our understanding of the pathogenesis of EBI-SAH, effective therapeutic strategies remain elusive. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and failure of antioxidant defense, has emerged as a key contributor to neuronal damage in EBI-SAH. This review aims to synthesize knowledge regarding the core molecular mechanisms of ferroptosis, focusing on its role in EBI-SAH initiation and regulation, and comprehensively evaluate diverse pharmacological agents that inhibit ferroptosis to mitigate EBISAH. Natural products (e.g., dihydroquercetin and ginsenoside Rd), synthetic ferroptosis inhibitors (e.g., ferrostatin-1 and deferoxamine), nanomedicines, and small molecules (e.g., melatonin and semaglutide) exert neuroprotective effects by targeting ferroptosis pathways, including the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, Nrf2 signaling, iron chelation, and lipid peroxidation suppression. The findings of this study underscore the therapeutic potential of ferroptosis inhibition as a novel strategy to ameliorate EBI-SAH and provide a foundation for future translational research.

With a prevalence of almost one in eight people, psychiatric disorders are increasing at an alarming rate due to changes in lifestyle, stress, and dietary habits. Current diagnostic and treatment strategies for psychiatric disorders remain suboptimal and ineffective. Nanomedicine offers a transformative solution by overcoming critical barriers such as the blood-brain barrier, poor drug solubility, low bioavailability, and systemic side effects. Various nanocarriers like polymeric nanoparticles, dendrimers, liposomes, solid lipid nanoparticles, and inorganic nanomaterials demonstrate enhanced brain targeting, controlled drug release, improved therapeutic efficacy, and minimize systemic side effects across a range of psychiatric conditions. Nanomedicine applications span various psychiatric conditions, including depression, anxiety, schizophrenia, and autism, offering innovative solutions like intranasal drug delivery and ligand-targeted delivery systems. These systems exhibit promise in bypassing the blood-brain barrier and achieving site-specific drug delivery. This review highlights the increasing burden of psychiatric disorders, the limitations of current treatments, and the promise of nanomedicine in overcoming drug delivery challenges. It emphasizes how nanotechnology can enhance the pharmacokinetics and pharmacodynamics of psychotropic drugs, enable targeted and synergistic therapies, reduce side effects, and ultimately advance more personalized and effective psychiatric care.

Introduction: Although research supports the benefits of Physical Exercise (PE) in treating adolescent depression, data remain limited regarding the most effective types, durations, and intensities of exercise. Moreover, most of the research conducted has focused on short-term outcomes, leaving a notable gap in understanding the long-term sustainability of these benefits. Evaluate the effectiveness of PE in alleviating depressive symptoms in adolescents diagnosed with major depressive disorder (CRD number: CRD42024585812).

Methods: The search was conducted from inception to July 2024 in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, and SPORTDiscus. Randomized Controlled Trials (RCTs) involving adolescents aged 10-19 years diagnosed with unipolar major depression were included. The intervention group participated in structured PE programs, whereas the control group did not have PE. Two authors independently conducted screening, data extraction, and risk of bias assessment. A data synthesis was performed using a random-effects model to calculate the Standardized Mean Differences (SMD) for continuous outcomes. Heterogeneity was assessed using the I2 statistic. Sensitivity and subgroup analyses were used to explore the effects of different PE modalities and the duration and intensity of the interventions.

Results: 13 RCTs: 759 adolescents in the PE group and 695 in the control group were obtained. PE significantly reduced depressive symptoms compared to the control (SMD=-0.55; p<0.01; I2=61%). Aerobic exercise showed the largest effect (SMD=-0.69), followed by resistance training (SMD=- 0.35) and whole-body vibration (SMD=-0.60). Moderate-intensity PE interventions lasting 30-60 minutes, 2-4 times/week, were associated with the greatest reductions in depressive symptoms.

Discussion: PE demonstrates considerable potential as an adjunctive strategy to pharmacological treatment for depression, suggesting its impact may be further enhanced when implemented alongside pharmacotherapy.

Conclusion: PE, aerobic exercise, and resistance training are effective interventions for reducing depressive symptoms in adolescents. Moderate-intensity exercise of 30-60 minutes offers substantial benefits.

Background: Alzheimer's disease (AD) is the primary cause of dementia and a significant threat to healthy aging. The prevalence of AD and other non-communicable diseases (NCDs) is significantly influenced by the progressive decline in physiological functions that is associated with aging.

Methods: This review summarizes the results of drug interventions for AD that have been conducted in the past five years, with a particular emphasis on Phase I, Phase III, and Phase IV clinical trials. Systematic investigations of clinical trial registries and databases were employed to identify clinical trials. A total of 106 Phase I, 52 Phase III, and 13 Phase IV trials were considered, excluding studies on devices, biologics, and diagnostic tests.

Results: This review summarizes a wide range of therapy approaches aimed at different facets of AD pathogenesis, including amyloid-beta aggregation, tau protein dysfunction, neuroinflammation, synapse loss, and metabolic dysregulation. AD's complex nature highlights the need for multi-target treatment strategies, which may encompass combination therapies and innovative targets that show potential in addressing the complex pathogenesis of AD.

Discussion: Current clinical studies demonstrate a variety of therapies aimed at various pathogenic processes of AD. Progress in therapeutic discovery, including synthetic molecules and bioactive natural materials, suggests potential strategies for successful AD treatment. The efficacy of natural products as therapeutic agents is especially significant because of their multi-target effects.

Conclusion: Effective strategies to prevent the progression of AD require a thorough comprehension of its complex pathophysiology. Current clinical studies are essential for discovering viable chemicals and treatment strategies to combat this multifactorial neurodegenerative disorder, AD.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to characteristic motor symptoms such as bradykinesia, tremor, and rigidity, as well as a range of non-motor manifestations including cognitive impairment, mood disturbances and autonomic dysfunction. Among the multiple cellular mechanisms implicated in PD, the dysregulation of autophagy has gained significant attention in recent years. Autophagy is a crucial intracellular degradation pathway responsible for the removal of misfolded proteins and damaged organelles, processes that are particularly relevant in neurodegenerative diseases. Impairment of autophagic flux contributes to the accumulation of toxic protein aggregates and cellular stress in PD. Rapamycin, a compound originally isolated from Streptomyces hygroscopicus, is a well-established inhibitor of the mechanistic target of rapamycin (mTOR), a central regulator of autophagy. Preclinical studies have shown that rapamycin can stimulate autophagic pathways by suppressing mTOR signalling, leading to increased expression of autophagy markers. These effects have been associated with reduced neuronal damage, improved motor performance and decreased accumulation of pathological proteins in PD models. This review provides an overview of current preclinical research on rapamycin's neuroprotective potential in PD through autophagy enhancement. Although findings are promising, translating these outcomes into clinical practice necessitates a thorough understanding of rapamycin's pharmacodynamics, optimal dosing strategies, potential side effects and long-term safety. Further research is essential to establish its therapeutic viability in human populations.

Ischemic stroke occurs when reduced or blocked blood flow prevents oxygen and nutrients from reaching brain tissue, resulting in neurological deficits. It is a leading cause of disability and death worldwide, with varying degrees of brain injury, from tissue damage to neuronal death and functional impairments. While restoring blood flow is necessary, it can worsen damage through oxidative stress, pro-inflammatory cytokines, apoptosis, blood-brain barrier disruption, cerebral edema, and hemorrhagic transformation. Neuroprotection plays a crucial role in reducing ischemic damage, with therapies targeting antioxidant, anti-inflammatory, and anti-ferroptotic pathways being essential. Current treatments for ischemia remain insufficient, and there is a lack of comprehensive reviews on drug candidates targeting this condition. This review aims to address this gap by evaluating 271 potential drug candidates for cerebral ischemia. It presents an in-depth analysis of compounds with core structures such as triazole, piperazine, pyrrole, amide, pyridine, and oxadiazole, along with functional groups like hydroxyl, halogen, and alkyl groups. These compounds exhibit promising neuroprotective, antioxidant, anti-ferroptotic, and anti-inflammatory effects. The encouraging findings highlight the need for further research and optimization to develop more effective therapeutic agents, reduce mortality, and prevent permanent disabilities associated with ischemic brain injuries.