Central nervous system agents in medicinal chemistry最新文献

Multiple sclerosis (MS) is an unceasing, demyelinating, idiopathic inflammatory, and neurodegenerative disease of the Central Nervous System (CNS.) The disease is characterized by the occurrence of neurological symptoms over a period of days to weeks, abide by partial or absolute diminutions of various durations. In this review, a concise outline on disease activity and progression of MS, pathogenesis with the special prominence on the biomarkers for the MS as therapeutic targets has been discussed by carrying out a comprehensive literature survey employing chief websites and search engines for investigation. Cortical inflammation, neurodegeneration, demyelination, axonal injury, axonal loss, oligodendrocytes, mitochondrial dysfunction, microglia activation, oxidative and nitrosative stress are the pathological hallmarks of the MS. CNS neurofilaments, chitinase and chitinase 3-like proteins, soluble circulating form (sCD163), Chemokine ligand 13 (CXCL13), immunoglobulin M, MicroRNA (miRNA) and messenger Ribonucleic Acid (mRNA), Glial fibrillary acidic protein (GFAP), serum osteopontin, 8-iso-prostaglandin F2α (8-iso-PGF2 α), apo-Lipoprotein E and myelinreactive T cells are some of the therapeutically valuable biomarkers for such multifarious disorder. MS is one of the chronic neurodegenerative diseases with undefined etiology. The study of the pathophysiology of the disease and the involvement of certain biomarkers can help identify new targets for therapeutic intercession, identify individuals at risk of developing the disease later in life, and allow more effective treatment of progressive diseases such as MS.

The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.

Background: Audiogenic Epilepsy (AEs) is a subtype of epileptic seizure that is generally caused by high-intensity sounds. A large number of traditional medicines has been explored in this lieu where our study chased Galium verum L. (Rubiaceae), an herbal plant which is commonly known as Lady's Bedstraw, that contains a highly rich chemical composition including flavonoids (Hispidulin, Quercetin, and Kaempferol), and phenolic acids (chlorogenic acid, caftaric acid, and gallic acid). G verum is well known for its antioxidant, neuroprotective, and anti-inflammatory properties. Recently, the unique role of Adhesion G Protein- Coupled Receptor V1 (ADGRV1) protein in the progression of audiogenic epilepsy has been explored.

Aim and objectives: This study aimed to examine the potent phytoconstituents of the hydroalcoholic extract of G. verum L. (HEGV) using analytical techniques. Additionally, our study sought to evaluate the antioxidant, neuroprotective, anti-inflammatory properties, and antiepileptic potency of HEGV by targeting ADGRV1 via in silico and in vitro analyses using SHSY5Y cells.

Method: HPLC and LC-MS techniques were employed to identify the flavonoids, iridoids, and phenolic acid derivatives present in HEGV. DPPH (2,2-diphenyl-1-picrylhydrazyl), nitric oxide (NO), and hydroxyl (OH) radical scavenging assays were performed to confirm the antioxidant potential of the extract. Additionally, in silico molecular docking and molecular dynamic studies were performed using AutoDock Vina software to analyze the possible interactions between crucial phytoconstituents of HEGV and ADGRV1, followed by cell line analysis. In the in vitro analysis, antioxidant, neuroprotective, and anti-inflammatory properties were assessed via cell viability assay, IL, GABA, and glutamate estimation.

Results: LC-MS and HPLC analyses revealed high concentrations of hispidulin, a major flavonoid found in HEGV. HEGV exhibited moderate-to-high free radical-scavenging activities comparable to those of ascorbic acid. Docking analysis demonstrated that hispidulin has a stronger binding affinity with ADGRV1 (Vina score = -8.6 kcal/mol) than other compounds. Furthermore, cell line analysis revealed that the MSG exacerbates the neurodegeneration and neuroinflammation, whereas, HEGV and Hispidulin both possess neuroprotective, antioxidant, and antiepileptic activities.

Conclusion: HEGV and Hispidulin proved to be promising candidates for treating audiogenic epilepsy by modulating ADGRV1.

Brain ischemia occurs following heart failure, thromboembolism, and atherosclerosis, and it is characterized by the disturbance of blood flow resulting from the blockage of blood vessels. After a series of studies, it is deduced that various changes occur following stroke, including neural death and changes in plasticity. Studies have reported that neurotransmitters tend to change following a stroke. These changes that occur surrounding the infarct area following a stroke can be considered new therapeutic targets for stroke rehabilitation. Although various studies have reported that different neurotransmitters have a promising role in either the progression or the rehabilitation following stroke, they have not found any pharmacological interventions to help the previous rehabilitation therapeutics. Phytocompounds also offer potential therapeutic benefits in stroke management due to their antioxidative and anti-inflammatory properties. This article aimed to compile recent advancements in neurotransmitter research related to ischemia and explore the potential use of neurotransmitter agonists/antagonists in ischemic conditions to identify potential drug candidates for treating the severe and prolonged stages of stroke in the future.

Background: Neuropathic pain is a complex chronic condition resulting from the damage or dysfunction of the nervous system. Conventional therapies offer limited success and often come with various adverse effects. Therefore, the exploration of alternative therapies, such as phytoconstituents, may be of substantial interest for their potential to alleviate neuropathic pain.

Objectives: This review systematically examines the diverse roles and mechanisms of various phytoconstituents in modulating neuropathic pain. In this study, a comprehensive analysis of phytoconstituents in neuropathic pain is carried out to understand their mechanism in preventing the disease.

Method: The current search is done in the databases of Google Scholar, PubMed Central, ScienceDirect, and Scopus using the keywords: neuropathic pain, phytoconstituents as analgesics, physiological effects of medicinal plants, and natural products, to find the most relevant articles of the last 10 years.

Result: Out of 125 articles, 112 were included in this study, which revealed that several phytoconstituents inhibit several biomarkers responsible for neuropathic pain. Moreover, this review highlights the underlying molecular pathways and targets through which these bioactive compounds exert their therapeutic effects, emphasizing their potential as novel pharmacological agents.

Conclusion: This study concludes that phytoconstituents may possess potential applications in managing neuropathic pain and could be effectively used as an alternative approach to mitigate the condition with enhanced risk of safety and tolerability.

Background: Aging affects cellular functions and impairs tissue homeostasis. Carvacrol, a polyphenolic compound, has been shown to exert a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer characteristics.

Methods: This investigation aimed to evaluate the effect of carvacrol in elderly male rats. Carvacrol at a dose of 15 or 30 mg/kg was administrated daily per os for 60 days to aged rats. The liver, heart, and kidney samples were taken for the analysis of oxidative stress markers. Serum samples were used to evaluate liver enzymes (alanine transaminase (ALT) and aspartate aminotransferase (AST)).

Results: The levels of malondialdehyde (MDA) in the liver, heart, and kidney tissues of aged rats were higher. Conversely, the level of thiol was lower in the mentioned tissues than in the young control group. The levels of MDA in the liver, heart, and kidney tissues of aged rats were significantly reduced by carvacrol, which was accompanied by increased levels of total thiol. ALT and AST levels were higher in the serum of aged rats than in the young control ones. Carvacrol decreased ALT and AST levels in the serum of aged rats versus aged control rats.

Conclusion: Carvacrol can be effective in protecting susceptible aged tissues and organs by increasing antioxidant defenses and decreasing liver enzymes.

Introduction and aim: Seizures due to epilepsy in any form cause a wide range of problems in a patient's physical, psychological, and social health. This study aimed to investigate piperine's anti-seizure and antiepileptic effects and mechanisms.

Methods: In this systematic review study, which was conducted according to the principles of PRISMA 2020, the initial search was conducted on November 2, 2023, using EndNote software. Various databases such as PubMed, Cochrane Library, Web of Science, Embase, and Scopus were searched using specific keywords. After screening the articles, a form was designed according to the objectives of the study, and the information related to the included articles was entered in the form, and the studies were reviewed.

Results: Piperine showed its antiepileptic activity by affecting the brain's antioxidant, anti-inflammatory, and anti-apoptotic activity. It also, by modulating brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA)ergic activity, can control seizures. In addition, piperine can help treat seizures and epilepsy by elevating 5-HT levels in the brain, modulating astrocyte and microglia function, modulatory effects on Ca2+ and NA+ channels, increasing antiepileptic drugs bioavailability and influencing protein and gene expression.

Conclusion: In vivo and in vitro studies showed beneficial effects on treating epilepsy. Although clinical studies also showed similar results, these needed to be increased, and more clinical studies needed to be designed in this field.

Background: The low effectiveness of existing pharmacotherapy strategies for Alzheimer's disease (AD) makes it necessary to develop a new concept for the treatment of this type of dementia. This search is promising to be carried out within the framework of the paradigm of targeting intracellular signaling pathways in Regenerative-Competent Cells (RCCs).

Objective: The purpose of the research is to study the impact of adenylate cyclase (AC) inhibitor on disorders of the psychoemotional status in aged male C57BL/6 mice, as well as on the dynamics of the content and functioning of RCCs nervous tissue.

Methods: We examined the effect of the AC inhibitor (2',5'-Dideoxyadenosine) on conditioned reflex activity, behavioral and emotional profile in a mouse AD model (16-month-old (aged) male C57BL/6 mice), as well as the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells in the subventricular zone of the cerebral hemispheres (SVZ).

Results: In aged C57BL/6 mice, we found impairments in exploratory behavior, emotional reactivity, and memory, which are the characteristics of senile dementia. Therapy based on AC inhibition led to an increase in the number of NSCs and NPCs in the SVZ due to an increase in their proliferative activity. These changes were more pronounced in NCPs. At the same time, a decrease in the specialization intensity was recorded in NSCs. These phenomena developed against the background of increased secretion of neurotrophic growth factors by oligodendrocytes and microglial cells. The neuroregenerative effects of 2',5'-dideoxyadenosine correlated with the correction of age-related disorders of the psychoemotional status in aged mice.

Conclusion: The results provide the basis for the development of targeted drugs based on AC inhibitors to stimulate neurogenesis as an approach for the effective treatment of AD.

Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-β protein (Aβ) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aβ, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aβ production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aβ production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research.