Central nervous system agents in medicinal chemistry最新文献

Background and aim: This study aims to investigate the antidepressant properties of Hispidulin, a flavonoid present in Scutellaria barbata D. Don. The selection of Hispidulin stems from its notable inhibitory activity against Xanthine Oxidase (XO), a parameter in the pathophysiology of depression.

Material and methods: Mice were subjected to a rigorous evaluation using a murine model of Chronic Unpredictable Mild Stress (CUMS) to induce depression for 21 days and antidepressant properties were rigorously assessed using the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Imipramine and fluoxetine were used as standard drugs. Additionally, neurochemical analyses were conducted to quantify serotonin (5-HT), norepinephrine (NE), and dopamine (DA) levels in the cortex, hippocampus, and hypothalamus. Further mechanistic insights were sought through the estimation of monoamine oxidase (MAO) activity and assessment of antioxidant enzyme levels in the brain. Plasma nitrite and corticosterone levels were also measured to delineate the underlying mechanism of action.

Results: Hispidulin demonstrated significant antidepressant effects, as evidenced by reduced immobility time in TST and FST and increased exploratory behavior in OFT. Neurochemical analysis revealed restoration of 5-HT, NE, and DA levels in key brain regions. Furthermore, Hispidulin modulated MAO activity and enhanced antioxidant enzyme levels in the brain. Plasma nitrite levels were elevated, indicating enhanced nitric oxide synthesis, while corticosterone levels were reduced.

Conclusion: Our findings indicate that Hispidulin exerts potent antidepressant effects, potentially mediated through its influence on monoaminergic neurotransmitters, MAO activity, and antioxidant defenses. These results provide valuable mechanistic insights into the antidepressant action of Hispidulin, supporting its potential therapeutic application in depressive disorders.

Aim: We aimed to conduct in silico screening of the potential phytoconstituent from a natural product database to find SIRT2 inhibitors.

Background: Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by behavioral and mental symptoms as well as a progressive loss of cognitive ability. Since SIRT2 may be detrimental to neurological illnesses, it is a prime target for research into SIRT2 inhibitors.

Objective: To identify the SIRT2 inhibitors and their role in AD.

Methods: We have utilized NPAtlas database and screened using pharmacophore-based virtual screening, molecular docking, and simulation. The Natural Products Atlas provides unrestricted access to various natural products derived from bacteria and fungi, allowing researchers to investigate and visualize the extensive chemical diversity in the natural world.

Results: From in silico screening data, we have found phytoconstituents that could function as SIRT2 inhibitors. Six phytoconstituents were identified using pharmacophore-based virtual screening. According to molecular docking, Kurasoin B outperformed the reference molecule regarding binding energy. Kurasoin B exhibited a binding affinity of -12.543 kcal/mol, whereas the binding affinity of the reference molecule was -12.089 kcal/mol. The Kurasoin B complex with SIRT2 was determined to be stable throughout the simulation by performing MD simulation, with an RMSD of 2.88 (Å), whereas the reference and free protein displayed RMSDs of 3.74 and 4.70 (Å), respectively.

Conclusion: In silico studies and data analysis, suggest that Kurasoin B may be able to suppress the SIRT2 protein for managing AD.

Background: Epilepsy is a critically deep-rooted CNS disorder affecting above 50 million people all over the world. Thus, a safe and effective treatment that proves its worth in this ailment is urgently needed. Thiazolidine-4-ones possess the molecules to be used as anticonvulsants. The thiazolidinedione is a cyclic analogue of thiosemicarbazides and thioureas as well as a (bio)isostere of hydantoin (imidazolidine-2,4-dione), which are recognized as novel anticonvulsant designs.

Aim: This study aimed to develop and evaluate a novel thiazolidine-4-one derivative by three-component condensation in one pot reaction method.

Methods: A novel thiazolidine-4-one derivative was formulated by three-component condensation. The selected OH (Alcohol) derivatives were found to be more potent; hence, a molecular docking study against a selected target LGI1 LRR domain was performed. Various analytical tests like FTIR and H1 NMR were accomplished. The FTIR was used to validate the existence of multiple functional moieties like C-S, O-H, C=O, C-N, N=O, C-NH, C-O in the wave region from 3075 cm-1 - 1236 cm-1 and H1 NMR was employed to ascertain if the synthesized analogues had the complete set of protons. Then, the anti-seizure activity of the selected compound was examined using PTZ models in mice at three successive doses, i.e., 25, 50, and 100mg/kg, and compared with standard ethosuximide.

Results: The docking simulations were initiated using PyMOL after the binding site was determined and the receptor and ligand were suitably prepared. It showed higher binding frequency in comparison to the standard marketed drug Ethosuximide. FTIR and H1 NMR spectroscopy were used to characterize the chemical components. Numerous functional groups, including O-H (alcohol), C=O (ketones), N=O, C-NH, C-N, C-S, and C-O bending stretching, were visible in the synthesized molecule accordingly. The synthesized compound was effective in inhibiting the convulsions at the concentration of 100 mg/kg.

Conclusion: The novel thiazolidine-4-one derivative showed promising activity and could be considered for further investigation and dosage form preparation.

The accumulation of tau-containing neurofibrillary tangles and beta-amyloid deposits has been identified as the hallmark of Alzheimer's disease. Alzheimer's disease (AD) is a hereditary and neurological condition that can result in non-amnestic cognitive decline in less common forms and amnestic memory loss in its classic form. While Alzheimer's disease is the most prevalent cause of memory loss in middle-aged and older adults, other neurodegenerative and cerebrovascular disorders can have an impact on the disease's clinical course. Designing multi-target-directed ligands (MTDLs) is a very promising modern approach. This methodology was designed specifically for treating disorders with complex pathological mechanisms. Among these disorders is Alzheimer's disease (AD), which is currently the most prevalent multifactorial neurodegenerative illness. Increased amounts of the amyloid βpeptide (Aβ) and hyperphosphorylated tau protein, together with the loss of neurons and synapses, are linked to Alzheimer's disease (AD). Additionally, there is evidence that the pathophysiology of this condition is influenced by oxidative stress, metal ion dysregulation, inflammation, and failure of the cell cycle regulatory system. Since Alzheimer's disease (AD) is a multi-factor illness, there are many attractive targets for the development of anti-AD medications. These molecules can be useful in treating AD since they are multi-target-directed. This review focuses on the discovery of dual and multi-acting anti-AD drug candidates, especially hybrids made by combining chemically active moieties that function against distinct targets. The first group of substances consists of cholinesterase inhibitors with extra properties or those that function as multiple binding site inhibitors. Natural products also provide numerous options for slowing the progression and symptoms of many diseases, including Alzheimer's Meanwhile, Natural chemical structures with the following characteristics: alkaloids, sterols, triterpenes, tannins, flavonoids, polyphenols, and antioxidants as well as anti-inflammatory and anti-amyloidogenic properties. We provide an overview of Alzheimer's disease pathophysiology and therapy targets in this study. We also show several isolated chemicals and medicinal plants that are used to treat and prevent the symptoms of Alzheimer's disease.

A small, translucent nematode known as Caenorhabditis elegans, or C. elegans, is frequently utilized as a model organism in biomedical studies. These worms, which are around 1 mm long and feed on bacteria, are usually found in soil. For accessible and effective research on genetics, developmental biology, neuroscience, cell biology, and aging, C. elegans provide an ideal model. Its simplicity, which includes a translucent body and a nervous system with only 302 neurons, makes it possible to see cellular and developmental processes in great detail. Because of its special benefits, the worm Caenorhabditis elegans allows for a thorough characterization of the cellular and molecular processes causing age-related neurodegenerative diseases. This is a general review of the life cycle, experimental methodologies, and the use of C. elegans to model brain diseases, including those related to molecular and genetic factors that cause neurodegenerative diseases. Additionally, we go over how C. elegans is a perfect model organism for studying neurons in instances of prevalent age-related neurodegenerative illnesses due to a combination of its biological traits and new analytical techniques. The literature review process was carried out step-by-step using online search databases such as Web of Science, PubMED, Embase, Google Scholar, Medline, and Google Patents. In the first searches, keywords like C.elegans, disease modelling, and neuroprotective activity were employed. Because of C. elegans's physiological transparency, it is possible to track the development of neurodegeneration in aging organisms by using co-expressed fluorescent proteins. Importantly, a fully characterized connectome provides a unique ability to precisely connect cellular death with behavioural instability or phenotypic diversity in vivo, thus permitting a deep knowledge of the detrimental effect of neurodegeneration on wellbeing. In addition, pharmacological therapies and both forward and reverse gene screening speed up the discovery of modifiers that change neurodegeneration. These chemical-genetic investigations work together to determine important threshold states that either increase or decrease cellular stress in order to unravel related pathways.

Brain-related Neurodegenerative Disorders (NDD) are the leading cause of low life expectancy globally. Brain-targeted drug delivery is required for treating most the NDD via bypassing the blood-brain barrier, and hepatic first-pass metabolism. The nasal-brain drug delivery route has the advantage of locally enhancing drug delivery to the brain, mainly through the olfactory route rather than systemic circulation. To overcome the limitations of nasal-brain drug delivery, a nanocarrier approach and mucoadhesive polymers are needed. Notwithstanding these constraints, various nanotechnology techniques have been created, including polymeric micelles, liposomes, polymeric nanoparticles, solid lipid nanoparticles, & nano-emulsions. This review aims to explore the intranasal pathway for drug delivery through the nasal-brain lymphatic systems, considering brain anatomy and physiology along with a drug formulation design approach.

Objective: Nattokinase (NK), a protease enzyme present in traditional fermented Japanese food, has shown fibrinolytic properties in vitro as well as in cardiac ischemia. In the present study, the Neuroprotective effect of standardized NK was evaluated in the thrombolytic focal cerebral ischemic model.

Methodology: The parameters of behavioural assessment, cerebral blood flow, inflammatory mediators, excitatory amino acids, and immunohistochemistry were measured to support the NK effect. NK was administered at 150 and 300 mg/kg, and its effects were compared with streptokinase (STK) (100μl/rat). Each mg of NK contains 5.5 Units of the enzyme, which can cause lysis of the fibrin.

Results: The results indicate that 7 days of treatment of 300 mg NK restored the cerebral blood flow and prevented the release of cytokine and excitatory amino acids. Similarly, neurological scores were reduced, and grip strength increased significantly with NK treatment. The GFAP and synaptophysin staining of the hippocampus (CA1) and cerebrum have shown recovery of neurons from ischemic damage in comparison to vehicle-treated ischemic-reperfused rats. The NK (300 mg/kg) fibrinolytic effect is comparable to STK treatment.

Conclusion: To conclude, NK, a serine protease, protects the brain from ischemic degeneration in thrombolytic cerebral ischemia. Consumption of this Japanese food might exhibit prophylactic activity.

The microbiota that inhabits the gastrointestinal tract has been linked to various gastrointestinal and non-gastrointestinal disorders. Scientists have been studying how the bacteria in our intestines have an effect on our brain and nervous system. This connection is called the "microbiota- gut-brain axis". Given the capacity of probiotics, which are live non-pathogenic microorganisms, to reinstate the normal microbial population within the host and confer advantages, their potential impact has been subjected to scrutiny with regard to neurological and mental conditions. Material sourced for this review included peer-reviewed literature annotated in the PubMed, Web of Science, Scopus, and Google Scholar databases. The result has indicated the integration of probiotics into a child's diet to enhance the neuro-behavioral symptoms. Notwithstanding this, the current data set has been found to be insufficient and inconclusive. The potential utility of probiotics for the prevention or treatment of neurologic and mental disorders has become a subject of substantial interest.

Migraine is one of the most painful and debilitating conditions, which is characterized by a pulsating headache. Many therapeutic strategies are being used to prevent and treat the symptoms and underlying pathology. A relatively high number of different medications are currently being used for migraine prevention in clinical practice. However, these compounds were initially developed for other indications and were different in their mechanisms of action. This review mainly summarized all the conventional and phytocompounds currently present for the treatment of migraine. Further, we also discussed therapeutic potential and clinical studies of natural compounds for the treatment of migraine prophylaxis under various chemical categories like flavonoids, polyphenols, alkaloids, glycosides, terpenoids, and lactone, acid, and alcohol.

This editorial discusses the toxicity and ethical concerns associated with the utilization of radiopharmaceuticals for diagnosing Alzheimer's disease. It highlights the potential benefits of using amyloid tracers during the early stages of diagnosing the disease. However, it also raises ethical concerns regarding the communication of this data to patients as well as their families. Additionally, it addresses the toxicity concerns associated with different radiopharmaceuticals, elucidating their potential to accumulate in bone and pose risks to the kidneys and bone marrow. We have examined the negative consequences, such as blood-related toxicity and suppression of bone marrow function, which have been recorded for different radiopharmaceuticals.