Central nervous system agents in medicinal chemistry最新文献

Introduction/objective: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by various neurobehavioral impairments. This study aims to review the preventive and therapeutic effects of Resveratrol (RSV) against ASD during various stages of life, specifically focusing on its influence on behavioral and neurodevelopmental biochemical mechanisms.

Methods: On December 6, 2024, a comprehensive electronic search was conducted across several high-coverage databases, including Web of Science, Scopus, PubMed/MEDLINE, Embase, and the Cochrane Library. The most important data were extracted and reviewed after screening the publications based on our inclusion and exclusion criteria.

Results: RSV alleviates autistic-like social behaviors by promoting social interaction and mitigating repetitive behaviors, anxiety, and symptoms resembling depression. RSV influences chemokine receptor expression, diminishes pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ), and regulates mitochondrial function by reducing nitrosative stress and thiobarbituric acid reactive substances (TBARS) levels, while also increasing antioxidant markers like glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) in the brain. Additionally, it enhances neuronal organization, increases the proportions of interneurons (SOM+, PV+, CB+), and restores the integrity of the hippocampus. Moreover, RSV modulates epigenetic pathways, such as estrogen receptorbeta (ERβ) activation and sirtuin 1 (Sirt1) expression, counteracts learning, memory, and locomotor activity deficits, and normalizes cortical oscillations. It also potentially modulated gutbrain- axis dysregulation and neurotransmitters.

Conclusion: RSV has shown promising effects on ASD, primarily through its influence on behavioral, neuromolecular, and neurodevelopmental mechanisms.

Background: Epilepsy is a common and frequently devastating disorder affecting millions of people. According to a recent survey, 1-2% of the Indian population suffers from major mental disorders and 5% suffers from minor mental disorders. Epilepsy is among those mental disorders that affect 30 million people worldwide. Currently, the treatment of epilepsy involves agents which modulate sodium-ion channels, enhance GABAergic transmission, and agents with multiple modes of action. Various classes of synthetic drugs are used to treat epilepsy, but these drugs are often challenged due to their unwanted side effects. Medicinal plants have been a part of human society which combating diseases from the dawn of civilization. The plant Cyanthillium cinereum (L.) H. Rob. is mainly found in the Himalayas from Kashmir to Nepal at an altitude of 8000 m. Decoction of this plant is traditionally used as an anti-cancer, anti-malarial, anti-epileptic, and in neurosis and skin diseases.

Objectives: The present study investigated the anti-epileptic activity of Cyanthillium cinereum leaves against pentylenetetrazole (PTZ)-induced epileptic model in mice.

Methods: Plant extracts were prepared using solvents in increasing polarity viz., petroleum ether, chloroform, ethanol, and water, using a Soxhlet apparatus. The bio-active extract was characterized using FTIR and GC techniques. In vivo antioxidants like GSH and SOD level, oxidative stress markers- MDA and hemoglobin and platelet count were also estimated in the animal brain.

Results: Amongst all extracts tested, only ethanol extract of Cyanthillium cinereum significantly (p<0.05) inhibited generalized tonic-clonic seizures in PTZ-induced epilepsy in mice in a dose (100 or 200 mg/kg., p.o.) dependent manner. The dose of 200 mg/kg of extract exhibited the most significant effect. It is also found that treatment with ethanol extract on PTZ-induced epilepsy in mice significantly (p<0.05) reduces the duration of convulsion and delays the onset of clonic convulsion.

Conclusion: The present findings suggest that the high amounts of phenols and flavonoids in the ethanol extract could be responsible for the anti-epileptic effect. Moreover, the ethanol extract also restored GSH, SOD and hemoglobin and platelet level and decreased oxidative marker- MDA content in the mice brain.

Diabetes can frequently result in peripheral diabetic neuropathy (PDN), a lifethreatening illness that impairs the motor and sensory abilities of peripheral nerves. Prompt identification and management of peripheral neuropathy are essential to avert permanent nerve impairment and enhance the well-being of affected individuals. In addition, axonal degeneration is usually detected at a late stage of the disease and serves as a basis for developing modern diagnostic techniques. Novel biomarkers that can detect PDN early and track its development are thus required. In this review, we highlight the most recent developments in identifying and verifying putative biomarkers for PDN, emphasizing their connections to the pathophysiology and clinical presentations of the illness. The challenges and opportunities for developing biomarker-based diagnostic and therapeutic strategies for PDN are also discussed. It is suggested that biomarkers help predict the response and outcome of PDN treatments, such as poly (ADP-ribose) polymerase inhibitors and regenerative medicine.

Background and objective: In stroke, reperfusion of blood to the cerebral ischemic area following sustained ischemia further exacerbates tissue damage, identified as cerebral ischemia and reperfusion (I/R) insult. Ischemic post-conditioning (IPoC) appears to offer benefits against I/R injury. The cascade of androgen receptors (ARs) has a vital role in cerebral stroke; however, its neurodefensive function in IPoC is unclear. This investigation aimed to explore the involvement of ARs in IPoC in cerebral I/R insult in rats.

Methods: Global cerebral ischemia/reperfusion (GCI/R) insult in experimental animals was provoked by 10 minutes of obstruction of the bilateral carotid arteries after reperfusion for 24 hours. IPoC was carried out by providing a triad of I/R insults with a gap of 10 minutes of GCI after 24 hours of reperfusion. Lateral push, inclined beam, rota rod, hanging wire, and Morris-water maze experimentations were conducted on animals to determine motor control and cognitive functions (learning and memory). Cerebral oxidative damage markers (raised lipid peroxidation and reduced glutathione levels), acetylcholinesterase (AChE) activity, inflammatory indicators (interleukin-6, interleukin-10, tumor necrosis factor-α, and myeloperoxidase), infarction, and histopathological alterations were also assessed.

Results: Animals with I/R exhibited reduced motor function and memory along with raised cerebral oxidative damage, AChE activity, inflammation, infarction, and histopathological alterations. IPoC after ischemic events recuperated the damaging outcomes of I/R insult. 60 minutes before cerebral ischemia, pretreatment with testosterone mimicked the neurodefensive outcomes of IPoC. However, neuroprotective outcomes developed by IPoC were diminished by flutamide (ARs antagonist) pretreatment.

Conclusion: IPoC may offer neuroprotective outcomes in I/R insult by modulation of ARmediated pathway.

The consumption and utilization of Ginkgo biloba leaves and seeds in traditional herbal treatments have left an indelible mark. Their rich chemical makeup and remarkable pharmacological effects, particularly in the form of EGb761 leaf extracts, have captivated researchers seeking novel treatments for degenerative nerve illnesses like Alzheimer's disease. However, the story of Ginkgo biloba doesn't end there. The Ginkgo biloba seeds, which were once highly regarded as sustenance and medicine but are often overlooked, hold ancient wisdom that awaits discovery and understanding, also, it is advised to consume one to two seeds per day because of the ginkgo toxin side effect. Traditional Chinese medicine has harnessed its potential to combat intestinal tract worm infections, pyogenic skin diseases, enuresis, asthma, cough, and more, owing to its abundant reserves of carbs, protein, fat, and polyphenols. Moreover, recent studies have emerged, suggesting their neuroprotective properties. Fostering awareness and encouraging the consumption of Ginkgo biloba seeds thus becomes paramount. As we embark on a quest to delve into the depths of Ginkgo biloba seeds, this comprehensive review aims to shed light on their key components, bioactivities, processing techniques, and the latest insights into their pharmacological actions. By embracing a holistic understanding of Ginkgo biloba seeds, we lay the foundation for their scientific advancement and the development of this remarkable edible seed. Furthermore, it is essential to acknowledge that while Ginkgo biloba holds immense potential, caution is warranted, as adverse effects such as allergies have been reported, particularly in individuals with known allergies.

Japanese encephalitis virus (JEV), first identified in 1935, continues to be a major threat to human health, especially in the Asia-Pacific region, where it remains prevalent. JEV, a neurotropic flavivirus, spreads through Culex tritaeniorhynchus mosquito bites and causes severe brain infections with high morbidity and mortality rates. Despite the availability of vaccines, no licensed anti-JEV drugs exist. This review provides a comprehensive overview of the epidemiology, structural and nonstructural proteins, and pathogenesis of JEV and explores potential drug targets. This study highlights both conventional and nonconventional drug targets, with a focus on nonstructural JEV proteins, which may hold promise for therapeutic development. This review also discusses drug targets shared by JEV and other flaviviruses, such as dengue, Zika, and West Nile virus, which reveal common pathways for viral entry and replication, along with distinct mechanisms specific to JEV. Key receptor interactions, including DC-SIGN, TAM receptor, sialic acid, LDLR, and CLEC5A interactions, are involved in JEV transmission and immune evasion. Additionally, the NMDA receptor has been identified as a critical player in JEV pathogenesis, suggesting new opportunities for neuroprotective therapies. A major obstacle in JEV drug development is the blood-brain barrier (BBB), which hinders the delivery of therapeutic agents to the central nervous system (CNS). Recent research has emphasized the need for innovative drug delivery systems that can cross the BBB, reducing viral replication and neural damage. While clinical trials with traditional antivirals have yielded mixed results, live attenuated and inactivated vaccines have shown promise in preventing JEV infection. Additionally, nucleic acid-based therapies, including microRNAs and short hairpin RNAs (shRNAs), are emerging as potential treatments, with nanoparticle-based delivery systems offering solutions to overcome BBB challenges. This review underscores the need for an integrated approach, including improved vaccines, targeted drug delivery strategies, and novel therapeutics, to effectively combat JEV infections on a global scale.

Background: The search for effective treatments for neurodegenerative diseases, particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts for 60-80% of dementia cases globally, affecting approximately about 50 million people. Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting significant attention from regulatory agencies, such as the US FDA.

Aim: This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's disease (AD) treatment using a novel network pharmacology approach. Specifically, it explored the interaction of dolutegravir with key molecular targets involved in AD pathology, predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic candidate.

Objective: This study employed a network pharmacology framework to evaluate dolutegravir, an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its possible therapeutic mechanisms.

Method: A network pharmacology approach was used to predict the drug targets of dolutegravir. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein- protein interaction (PPI) network analysis was conducted to assess key interactions and molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the predicted targets.

Result: PPI network analysis revealed that dolutegravir interacted with several key targets, including BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8, CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol).

Conclusion: The findings indicated that dolutegravir holds significant potential in modulating key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's established pharmacological profile, offers a promising route for accelerated therapeutic development in AD.

Objective: Major Depressive Disorder (MDD) is a psychiatric disorder that has a tight connection to stressful experiences, decreased levels of endogenous antioxidants and enhanced levels of oxidative stress. We drafted this research to define the results of combining agmatine and melatonin on stress-induced depression in mice.

Methods: Experimental groups included the non-stressed group treated with vehicle (ethanol at a concentration of 0.0005%), stressed vehicle (ethanol at a concentration of 0.0005%)-treated group, group treated with fluoxetine (10 mg/kg/day), group treated with melatonin (10 mg/kg/day), group treated with agmatine (1 mg/kg/day), group receiving a combination of melatonin (10 mg/kg/day) and agmatine (1 mg/kg/day). The animals were subjected to restraint stress for two hours daily for a duration of one week, concurrently with the daily oral administration of agents through drinking water. Open field test and forced swimming test were operated on the 8th day. The oxidative stress markers were measured in the mice hippocampus.

Results: Stress led to the elevation of immobility time. The combination group showed a significant effect in comparison to the agmatine and melatonin groups. The combination of melatonin and agmatine was successful in the elevation of hippocampus catalase activity; and this effect was comparable in the fluoxetine group. We observed enhancement of superoxide dismutase activity in treatment groups and reduction in malondialdehyde levels in melatonin, agmatine and combination groups.

Conclusion: A combination of agmatine and melatonin improves stress-induced depression more effectively than each alone, which may result from suppressing oxidative stress.

Background: The pharmacophoric approach relies on the theory of possessing ubiquitous chemical functionalities, and carrying a uniform spatial conformation that provides a route to enhanced potency on the same target receptor. JNK3, also known as c-Jun N-terminal kinase 3, is a protein kinase that plays a crucial role in various cellular processes, particularly in the central nervous system (CNS). In this study, a kernel-based partial least square (KPLS)- based Two-dimensional Quantitative structural activity relationship (2D QSAR) model to predict pharmacophores responsible for c-Jun-N-terminal kinase 3 (JNK3) inhibition.

Method: A library of small molecule JNK3 inhibitors was created from the literature, and a predictive model was built using Canvas 2.6.

Result: The analysis revealed key structural determinants of activity. Compounds with high pIC50 values (>6) showed numerous favorable contributions, particularly secondary benzamide nitrogen and methylene groups. Steric effects were more influential than inductive effects, with bulkier groups like t-butyl reducing activity. Positive contributions were observed with OH, OCH3, and -F substituents, while unfavorable effects were linked to tertiary nitrogen, methyl, and primary amino groups. Substituted sulphonamides and benzotriazole moieties enhanced activity unless modified with amino or carbonyl groups. Favorable contributions were noted for terminal heterocyclic rings like pyrimidinyl acetonitrile, whereas phenyl substitutions and certain piperazine configurations were detrimental. Hydrogen in the urea moiety and avoiding bulky substitutions were crucial for activity. These insights guide the design of potent JNK3 inhibitors.

Conclusion: The present study highlights the significant impact of substituents on molecular activity, with steric effects, particularly on the phenyl ring, playing a dominant role. Favorable contributions are linked to substitutions like hydroxyl, methoxy, and fluorine, while bulky and meta substitutions reduce activity. Functional groups like unsubstituted sulfonamide or free hydrogen in urea are crucial for activity. Insights into steric, electronic, and positional factors, combined with analysis of JNK3 inhibitors, will guide the design of more selective molecules.

Introduction: Ischemic stroke remains one of the leading causes of death and physical and mental disability. Oxidative stress, free radicals, and inflammation play critical roles in ischemic brain damage. Free radical scavengers such as edaravone and dimethyl fumarate (DMF), known for their antioxidant and anti-inflammatory properties, are considered promising targets for ischemic stroke treatment. This study aimed to assess the impact of these drugs on brain ischemia.

Methods: Forty-nine rats were randomly divided into seven groups: sham, edaravone, and DMF controls, as well as edaravone, DMF 5, 15, and 30 groups. Middle cerebral artery occlusion (MCAO) was induced in all groups except the sham group. The MCAO groups were administered with either the vehicle, edaravone (3 mg/kg), or DMF at doses of 5, 15, and 30 mg/kg twice daily for 14 days. Neurobehavioral assessments were conducted throughout the experiment, and anatomical changes in the brain were evaluated using stereological methods.

Results: Edaravone and three doses of DMF improved neurobehavioral functions. All treated rats showed a reduction in the ischemic volume and cell loss in the brain regions when compared with the control animals. MCAO reduced the total number of neurons and just DMF doses had a significant effect on this factor. Interestingly, MCAO increased the number of non-neurons and only the DMF 30 group significantly decreased this parameter. DMF 30 was more effective in ischemic stroke.

Conclusions: Although edaravone improved neurological functions and reduced the size of brain ischemia and cell loss, DMF, especially at higher doses, exerted a more beneficial effect on these parameters. Therefore, DMF could be proposed as a reinforcement to currently conventional therapies.