Central nervous system agents in medicinal chemistry最新文献

Introduction: Schizophrenia and schizoaffective disorder are generally treated with second- generation antipsychotic drugs. These drugs are mostly dopaminergic (D2) and serotonergic (5-HT2A) antagonists. They sufficiently improve positive schizophrenia symptoms; however, they ameliorate negative symptoms and cognitive functions only to a limited extent.

Material and methods: We review novel antipsychotic drugs that exert partial agonism at dopaminergic and serotonergic receptors, such as cariprazine, brexpiprazole, and lumateperone. In addition, the mechanisms of action of non-dopaminergic antipsychotic drugs are described. Updated neural network models are used to explain the mechanisms of action of muscarinic (M4 and M1) receptor agonists (e.g., xanomeline combined with trospium) and trace-amine-associated receptor 1 (TAAR1) agonists (e.g., ulotaront). Phase 3 clinical trials of new third-generation antipsychotic drugs are also presented.

Results: Novel antipsychotic drugs with partial agonism at D2 and D3 receptors improve positive and negative schizophrenia symptoms, as well as cognitive symptoms, more effectively than second- generation antipsychotic drugs. They are also well tolerated. M4 and M1 receptor agonists (i.e., xanomeline combined with trospium or emraclidine) and TAAR1 agonists (i.e., ulotaront) substantially improve negative schizophrenia symptoms and cognitive functions. These new nondopaminergic antipsychotic drugs better ameliorate negative symptoms and improve cognitive functions compared with second-generation antipsychotic drugs.

Discussion: Results from phase 3 clinical studies indicate the clinical efficacy of new thirdgeneration antipsychotic drugs.

Conclusion: Promising new antipsychotic drugs include cariprazine, brexpiprazole, lumateperone, ulotaront, and xanomeline combined with trospium. Phase 3 clinical studies have shown therapeutic effects superior to those achieved with second-generation antipsychotic drugs.

Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.

Schizophrenia (SZ), a chronic psychiatric disorder, presents significant challenges in its management, primarily due to its complex etiology and the limitations of current antipsychotic therapies. Traditional antipsychotics often alleviate positive symptoms but exhibit limited efficacy for negative and cognitive symptoms, alongside notable adverse effects. This has led to an increasing exploration of herbal remedies as complementary or alternative approaches. The review highlights the function of medicinal plants and phytochemicals in SZ management. The highlighted neuroprotective, antioxidant, anti-inflammatory, and receptor-modulating characteristics of plant-based compounds, such as alkaloids, glycosides, terpenes, and polyphenols, target critical neurotransmitter systems, including dopaminergic, serotonergic, and GABAergic pathways. Key examples, such as Mitragyna speciosa, Withania somnifera, and Ginkgo biloba, demonstrate the potential to mitigate SZ symptoms through mechanisms like oxidative stress reduction and receptor modulation. Furthermore, the synergistic effects of these herbs, when used as polyherbal formulations, as exemplified by traditional remedies like Yokukansan and Suoquan pill, underscore the therapeutic potential of combining multiple herbs. While promising, challenges remain in standardizing herbal preparations and validating their efficacy through rigorous clinical trials. The review consolidates the current understanding of phytoconstituents and herbal formulations, advocating for their potential integration into mainstream psychiatric care.

Introduction: Mental problems are associated with early neonatal and in utero exposure to maternal stress. With established negative impacts on mental health and cognitive function, road traffic noise (RTN) has emerged as a ubiquitous environmental stressor. In this work, we have examined the effects of maternal exposure to RTN on the development of neurogenesis and spatial memory in the hippocampus (HC) of offspring and investigated possible strategies for mitigating these effects.

Method: During the prenatal maturation stage, female Sprague Dawley (SD) rats that were determined to be pregnant were exposed chronically to 100 dB SPL (sound pressure level) RTN for six hours per day. The Morris water maze and elevated plus maze tests were used to evaluate the neurobehavioral performances of the offspring. The oxidative stress and neurogenesis in the HC were evaluated using 2% 2,3,5-triphenyl tetrazolium chloride staining, HC histopathology, and biochemical methods (SOD: superoxide dismutase, GSH: glutathione, CAT: catalase, as well as TBARS: thiobarbituric acid reactive substance, MPO: myeloperoxidase, and AChE: acetylcholinesterase), respectively. Additionally, we looked at the potential therapeutic benefits of melatonin, edaravone, and an enriched environment.

Result: The results of our investigation showed that maternal exposure to 100 dB SPL RTN considerably reduced the offspring's spatial memory and caused distress. The biochemical estimation of HC tissue supernatant revealed a considerable increase in MPO, AChE, and TBARS levels and a marked reduction in SOD, CAT, and GSH levels. However, there were notable protective effects against these unfavorable outcomes due to the administration of melatonin and edaravone, as well as from being exposed to an enriched environment.

Discussion: In our study, prenatal exposure to 100 dB SPL RTN caused oxidative stress, which caused neurodegeneration, as well as decreased spatial memory and induced anxiety, being consistent with previous findings. In particular, compared to offspring of the 100 dB SPL RTNexposed group, offspring of the maternally treated EDV and MLT combination groups showed superior spatial memory function, reduced anxiety, and increased neurogenesis.

Conclusion: The findings of our study have offered promising pathways for public health policies and urban planning concerns, as well as useful insights into the development of tailored therapies to safeguard against the cognitive and neurological repercussions of maternal RTN exposure.

Carvacrol is a major active compound present in the essential oils of various aromatic plants. Research strongly indicates that carvacrol holds considerable promise for use in the development of new pharmaceutical drugs and dietary supplements. Due to its broad spectrum of bioactive properties, carvacrol shows potential therapeutic applications for several complex and challenging brain-related disorders. Its actions are multifaceted; it mitigates neuroinflammation and exerts antioxidant properties as well as other neuroprotective effects that shield neural structures from degeneration. Additionally, carvacrol influences important neural systems, including the cholinergic and dopaminergic pathways, helping to regulate neurotransmitter levels and activity in ways that could mitigate neurological symptoms. Furthermore, its anti-apoptotic effects suggest that it can help prevent programmed cell death, a common factor in neurodegenerative diseases. Collectively, these biological properties make carvacrol an attractive option for use as an adjunctive or supportive therapy in managing a range of brain illnesses, including epilepsy, anxiety, depression, stroke, Parkinson's disease, and Alzheimer's disease. This study presents an extensive review of in vitro as well as in vivo research studies on carvacrol's protective effects across different brain disorders. By examining these studies, this review offers a comprehensive and up-to-date assessment of the biological activities and molecular mechanisms of carvacrol, emphasizing its potential role in therapeutic strategies aimed at supporting brain health and treating complex neurological conditions.

Introduction: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment.

Methods: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes.

Results: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress.

Discussion: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents.

Conclusion: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.

Alzheimer's disease (AD) remains one of the most pressing neurodegenerative disorders worldwide, with increasing prevalence and limited disease-modifying treatments. While recent clinical advances, including monoclonal antibodies like lecanemab and donanemab (early stage), show promise in slowing cognitive decline by targeting amyloid-beta pathology, their use is associated with risks such as amyloid-related imaging abnormalities (ARIA). Alongside these developments, preclinical innovations continue to explore novel mechanisms, including antisense oligonucleotides, TREM2 agonists, siRNA, mRNA-LNP platforms, and CRISPR-based gene editing. These approaches target tau aggregation, neuroinflammation, and genetic risk modifiers like APOE4. This review bridges the gap between preclinical research and clinical application by highlighting the mechanisms, therapeutic potential, and translational challenges of both established and emerging therapies. Emphasis is placed on biomarker-guided trials, model systems (e.g., iPSC organoids), and future directions to improve efficacy, safety, and global accessibility of AD therapeutics.

Neuropathy is a disorder defined by injury or dysfunction of the peripheral nerves, which causes a variety of symptoms, including pain, numbness, and weakness. Diabetes, autoimmune illnesses, infections, and chemotherapy are some of the possible underlying reasons. Polysaccharides, complex carbohydrates derived from diverse natural sources such as plants, fungi, algae, and microbes, have garnered a significant role for their multifaceted biological activities that have been shown in humans, such as the ability to bind nuclear receptors, control inflammation, and scavenge radicals and antioxidants. These properties make polysaccharides a potential therapeutic option for preventing and managing neuropathy. Many polysaccharides possess strong antioxidant properties, which can help protect neurons from oxidative stress. Moreover, they have a broad variety of biological actions, including antibacterial and anticancer properties, as well as preventive effects against neurological illnesses, including neuropathy, Alzheimer's, and Parkinson's disease. Because of their diverse spectrum of biological functions, they have drawn a lot of attention for their potential as therapeutics, including nerve regeneration and repair, neuroprotective, antioxidants, and reducing inflammation. Several studies have emphasized the significant potential of polysaccharides for enhancing nerve regeneration. This review investigates numerous natural sources of polysaccharides, the mechanism of action, and their therapeutic potential for neuroprotective or neuropathy management, offering insights into their potential role in enhancing patient outcomes and quality of life. This review also underscores the therapeutic potential of polysaccharides as adjunct or alternative agents in neuropathy management and advocates for further clinical validation and mechanistic investigations.

Introduction: Pseudoelephantopus spicatus has been traditionally employed in ethnomedicine for treating a variety of ailments. However, its neuroprotective and antioxidant properties remain underexplored. This study investigates the phytochemical composition, antioxidant potential, and neuropharmacological effects of its methanolic leaf extract (MEPS).

Method: Leaves were collected, identified, and subjected to methanolic extraction. Phytochemical profiling was conducted via GC-MS, and antioxidant activity was assessed using DPPH and superoxide scavenging assays. Swiss albino mice were employed in behavioral tests, Hole Board Test (HBT), Elevated Plus Maze (EPM), Forced Swimming Test (FST), and Tail Suspension Test (TST) to evaluate anxiolytic and antidepressant effects. Additionally, in silico molecular docking assessed interactions of major compounds with the GABA receptor.

Results: GC-MS revealed key phytochemicals, including 9,12-octadecadienoic acid and hexadecanoic acid methyl ester. MEPS showed moderate antioxidant activity with 13.264 mg GAE/g and 43.692 mg QE/g for phenolics and flavonoids, respectively. Behavioral assays showed dosedependent anxiolytic and antidepressant effects, especially at 200 mg/kg (p < 0.001). Docking studies indicated strong GABA receptor binding, particularly for 9,12-octadecadienoic acid (-6.6 kcal/mol).

Discussion: The neuropharmacological effects are attributed to high flavonoid content and specific phytochemicals with known CNS activity. The behavioral improvements and antioxidant activities support MEPS's therapeutic potential in neurological disorders, likely through modulation of oxidative stress and GABAergic pathways.

Conclusion: MEPS exhibits significant antioxidant, anxiolytic, and antidepressant activities, supported by both in vivo and in silico findings. These results validate its traditional use and warrant further studies for its potential development as a neuroprotective agent.